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WO2025248390A1 - Process for the preparation of thiophene compounds - Google Patents

Process for the preparation of thiophene compounds

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Publication number
WO2025248390A1
WO2025248390A1 PCT/IB2025/055302 IB2025055302W WO2025248390A1 WO 2025248390 A1 WO2025248390 A1 WO 2025248390A1 IB 2025055302 W IB2025055302 W IB 2025055302W WO 2025248390 A1 WO2025248390 A1 WO 2025248390A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
formula
oxo
thiophenecarboxylate
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/055302
Other languages
French (fr)
Inventor
Prashant KINI
Jalindar Totre
Mahesh BHAVSAR
Kiran LINGAYAT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UPL Ltd
Original Assignee
UPL Ltd
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Filing date
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Publication of WO2025248390A1 publication Critical patent/WO2025248390A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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 present invention relates to a process for preparation of thiophene compounds.
  • the present invention more particularly relates to preparation of methyl tetrahydro- 5-methyl-4-oxo-3 -thiophenecarboxylate and methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate.
  • Thiophenes are one of the commonly found heterocyclic ring systems in many biologically active compounds that have found significant applications in different disciplines.
  • various substituted thiophenes and derivatives such as esters of thiophene compounds have been designed and synthesized as drug-like candidates with different pharmacological actions and therapeutic products. They are also widely used as important building blocks in many agrochemical products including herbicides.
  • Substituted 4-alkoxycarbonyl-3-aminothiophenes are prepared from alkoxycarbonyl-3 -thiophenes which can be prepared from dialkyl mercapto esters.
  • The’963 patent discloses preparation of Methyl 2-[(3-methoxy-3-oxopropyl) sulfanyl] propanoate from ethyl-2-bromopropionate as a starting material.
  • the product obtained in the’963 is then further cyclised to get methyl 5-methyl-4- oxotetrahydrothiophene-3-carboxylate, which is another intermediate compound used for the synthesis of pharmaceutically and agrochemically active compounds.
  • It is an object of the present invention is to provide a process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I).
  • Formula (I) Yet another object of the present invention is to provide Thiencarbazone-methyl of Formula (II), prepared from the compound of Formula (I) of the present invention. It is another object of the present invention to provide a clean, efficient and industrially viable process for the preparation of thiophene compounds.
  • Lg is a leaving group selected from -X (halogen atom), o-mesylate group, or o-tosylate group.
  • Another aspect of the present invention is to provide a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (I) comprising: reacting compound of Formula (III) with methyl-3-mercaptopropionate of Formula (IV) in presence of a base, Formula (III)
  • Another aspect of the present invention is to provide compound of Formula (V) substantially free from, Ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
  • Another aspect of the present invention is to provide a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (I) comprising the steps of: i. reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula (IV) in presence of a base,
  • Formula (III) Formula (IV) to give Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V).
  • Formula (V) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group, ii. treating said compound of Formula (V) of step i) with base to form methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula
  • Yet another aspect of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II),
  • Yet another aspect of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II),
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
  • impurities refers to one or more unreacted synthetic intermediates, reagents, solvents, organic and/or inorganic products of side reactions, organic and/or inorganic salts and/or other undesired materials.
  • substantially free from impurities refers to Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V); Methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I) or Thiencarbazone methyl of Formula (II) containing less than about 3.0 % or less than about 2.0 % or less than about 1.0 % of one or more impurities.
  • room temperature refers to the temperature in the range of 20°C to 35°C.
  • the present invention provides a process for the preparation of Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), Formula (I) comprising; reacting compound of Formula (III)
  • Lg is a leaving group selected from -X (Halogen atom), o-mesylate group or o-tosylate group.
  • the compound of Formula (III) is selected from methyl 2- bromopropanoate, methyl-2-chloropropanoate, Methyl-2-(methanesulfonyloxy) propanoate, or Methyl 2-[(4-tolylsulfonyl)oxy]propionate.
  • the compound of Formula (III) is methyl-2-chloropropanoate.
  • the base used for the reaction is selected from the group comprising alkali metal alkoxide or alkaline earth metal alkoxide or the mixture thereof.
  • the base used for reacting the compound of Formula (III) with methyl-3 -mercaptopropionate of Formula (IV) is selected from alkali metal carbonates, hydrides, alkoxide of hydroxides, such as sodium, potassium and lithium hydroxide, and the alkaline earth metal hydroxides, such as barium, calcium and magnesium hydroxide or organic bases including but not limited to amines, cyclic, acyclic or caged, alone or as a mixture with bases prepared from alkali metals; the preferred base is alkali metal alkoxide , such as sodium methoxide.
  • the base used for reacting compound of Formula (III) with methyl-3-mercaptopropionate of Formula (IV) is 1.0 to 2.0 equivalent with respect to the compound of Formula (III), preferably 1.0 to 1.5 equivalent of base is used.
  • reaction of compound of Formula (III) with compound of Formula (IV) is carried out in a solvent selected from alkanols which are straight or branched chain alcohols having 1-20 carbon atoms, preferably lower alkanols having 1-6 carbon atoms such as methanol, ethanol, propanol, isopropanol, more preferably methanol is used as a solvent.
  • alkanols which are straight or branched chain alcohols having 1-20 carbon atoms, preferably lower alkanols having 1-6 carbon atoms such as methanol, ethanol, propanol, isopropanol, more preferably methanol is used as a solvent.
  • the reaction is carried out in an alkanol solvent selected from the group comprising of methanol, ethanol, propanol, isopropanol or mixture thereof.
  • reaction of compound of Formula (III) with compound of Formula (IV) is carried out at about -5°C to about 10°C.
  • reaction is carried out at about 0°C to about 5 °C.
  • the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (III) Formula (IV) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group; and, wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
  • reaction is carried out with or without isolating Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V).
  • methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) or Methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), prepared according to the present invention is substantially free from impurities.
  • methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) or Methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), prepared according to the present invention is substantially free from impurities, wherein the said impurities are ethyl 2-[(3- methoxy-3-oxopropyl)thio]propanoate, Methyltetrahydro-5-Ethyl-4-oxo-3- thiophenecarboxylate or mixture thereof.
  • the present invention provides the process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (I) comprising: reacting methyl-2-chloropropanoate of Formula (Illa)
  • the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (I) comprising: reacting methyl-2-chloropropanoate of Formula (Illa) with methyl-3- mercaptopropionate of Formula (IV), in presence of a base, Formula (Illa)
  • the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
  • Formula (I) comprising the steps of : i. reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula (IV) in presence of a base,
  • methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) of step i) is isolated after completion of the reaction.
  • step ii) of the process is carried out with or without isolating compound of Formula (V).
  • the compound, methyl 2-[(3-methoxy-3-oxopropyl)thio] propanoate of Formula (V) of step i) is isolated and used for preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I).
  • the compound methyl 2-[(3-methoxy-3-oxopropyl)thio] propanoate of Formula (V) of step i) is not isolated and taken for further reaction.
  • step ii) is carried out in presence of base selected from the group comprising alkali metal alkoxide or alkaline earth metal alkoxide or the mixture thereof.
  • methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V) is treated with a base in a solvent to obtain methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I).
  • the base used in step ii) for treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) is selected from alkoxide of alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkoxide of alkaline earth metal hydroxides, such as barium hydroxide, calcium hydroxide and magnesium hydroxide; or organic bases including but not limited to amines, cyclic, acyclic or caged, alone or as a mixture with bases prepared from alkali metals; the preferred base is alkali metal alkoxide, such as sodium methoxide.
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide
  • alkoxide of alkaline earth metal hydroxides such as barium hydroxide, calcium hydroxide and magnesium hydroxide
  • organic bases including but not limited to amines, cyclic, acyclic or caged, alone or
  • the alkoxide of alkali metal hydroxides or alkaline earth metal hydroxides used for treating methyl 2-[(3-methoxy-3-oxopropyl) thio]propanoate of Formula (V) to get methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I) is 0.95 to 3.0 equivalent; preferably 1.0 to 2.0 equivalent is used.
  • step ii) of the reaction is carried out in a solvent selected from aliphatic or aromatic hydrocarbons; aliphatic or aromatic halogenated hydrocarbons.
  • the solvent used for treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) to get Methyl tetrahydro-5-methyl-4- oxo-3-thiophenecarboxylate of Formula (I) is selected from, aliphatic hydrocarbons such as pentane, n-hexane, n-heptane or aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform or aromatic hydrocarbons such as benzene, toluene, xylene, halogenated aromatic hydrocarbons such as monochlorobenzene, dichlorobenzene, and the like.
  • the preferred solvent is an aromatic hydrocarbon, such as toluene.
  • step ii) reaction of treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) to get methyl tetrahydro-5-methyl-4- oxo-3-thiophenecarboxylate of Formula (I) is carried out at a temperature in the range from about 25 °C to about 100°C. In yet another embodiment step ii) reaction is carried out in the range of about 50°C to about 80°C.
  • reaction is carried out for a period from 6 to 10 hours, preferably 6 to 8 hours.
  • the present invention provides a process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), wherein the process proceeds via preparation of methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
  • the present invention provides a process for the preparation of thiencarbazone-methyl of Formula (II) comprising; a) preparing methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V), substantially free from undesired impurity Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate; b) preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) using methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V), substantially free from undesired impurity Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate; and c) converting methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) to
  • the present invention provides a process of preparing thiencarbazone-methyl of Formula (II),
  • Formula (II) comprising: reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula
  • Lg is a leaving group selected from X (halogen), o-mesylate, o-tosylate; and converting methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula
  • the present invention provides the process of preparing thiencarbazone-methyl of Formula (II),
  • Formula (II) comprising reacting methyl-2-chloropropanoate of formula (Illa) with methyl-3- mercaptopropionate of Formula (IV) in presence of a base to get Methyl tetrahydro- 5-methyl-4-oxo-3 -thiophenecarboxylate of Formula (I) and
  • Formula (Illa) Formula (IV) Formula (I) converting Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), to thiencarbazone-methyl of Formula (II).
  • the conversion of methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate of Formula (I) to thiencarbazone-methyl of Formula (II) is carried out via processes known by the skilled person.
  • the conversion of methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate of Formula (I), to thiencarbazone-methyl of Formula (II) is carried out by a process comprising the steps of: i) converting compound of Formula (I) to compound of Formula (VI) under heating,
  • Yet another embodiment of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II), Formula (II) wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
  • Thiencarbazone methyl of Formula (II), prepared according to the present invention is substantially free from impurities.
  • Thiencarbazone methyl of Formula (II), prepared according to the present invention is substantially free from impurities, wherein the said impurities are ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate, Methyl tetrahydro-5-Ethyl-4-oxo-3-thiophenecarboxylate or mixture thereof.
  • Thiencarbazone methyl of Formula (II), prepared according to the present invention contains less than about 3.0 % ethyl 2- [(3-methoxy-3-oxopropyl)thio]propanoate, methyl tetrahydro-5-Ethyl-4-oxo-3- thiophenecarboxylate or mixture thereof.
  • the present process is simple, efficient and enables production on an industrial scale.
  • the present process provides the intermediate and desired compounds in good yield and high purity.
  • the present invention provides highly pure methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), significantly substantially free from impurities.
  • Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) according to patent US4428963: a) Preparation of Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V): Methyl-3 -Mercapto propionate (132.58 g 1.1 moles) was charged in methanol (100 ml) to make a solution. The reaction mixture was cooled to 0°C to 5 °C and added 25 % methanolic solution of sodium methoxide solution (240 ml).
  • Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V) (121.4 g; 0.552 moles), as obtained in 2-a) as a solution in dry benzene (90 ml ) was added to dropwise to a suspension of anhydrous sodium methoxide (30 g) in dry benzene (200 ml). The reaction was allowed to proceed overnight. The mixture was partitioned between water and ether. The aqueous phase was then acidified to pH 1 with 6 N HC1 and extracted three times with methylene chloride.
  • Methyl-3 -Mercapto propionate (7 kg; 50 moles) in methanol (7 L) was charged to the reactor and 30 % methanolic solution of sodium methoxide (10.320 kg) was added to it in 3 to 4 hours at room temperature. Stirred the reaction mass at this temperature for 1 hour.
  • methyl-2- chloropropionate (7.110 kg; 58.017 moles) was added as a solution in methanol (4.67 L) at 0°C to 5 °C in 4 hours and continued stirring at this temperature for 1 hour.
  • Methanol was distilled out under vacuum.
  • dichloromethane and water was added to make clear solution at 20°C to 25 °C. The layers were separated, solvent was distilled out to get the title compound (11.98 kg) as an oily product. (Yield: 99.7% and purity 95.7%).
  • the separated aqueous phase was re-extracted with dichloromethane.
  • the oraganic layers were combined and -30 % dichloromethane was recovered by distillation at 40-50°C.
  • the organic layer was cooled to 15-20°C and ammonium carbonate (1.9 kg) was added to this in portion wise within 1-2 hours.
  • the reaction mass was stirred for 6 hours. After completion of the reaction, the reaction mass was diluted with water.
  • the layers were separated, the aqueous layer was re-extracted with dichloromethane.
  • the combined organic layer was concentrated to get 1.2 kg yellowish title compound (Purity: 96.68 %) iii.

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Abstract

The present invention relates to a process for preparation of thiophene compounds. The present invention more particularly relates to preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), and methyl 2-[(3-methoxy-5 3-oxopropyl)thio]propanoate of Formula (V), substantially free from impurities.

Description

PROCESS FOR THE PREPARATION OF THIOPHENE COMPOUNDS
Field of the invention
The present invention relates to a process for preparation of thiophene compounds. The present invention more particularly relates to preparation of methyl tetrahydro- 5-methyl-4-oxo-3 -thiophenecarboxylate and methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate.
Background of the invention:
Thiophenes are one of the commonly found heterocyclic ring systems in many biologically active compounds that have found significant applications in different disciplines. In addition, various substituted thiophenes and derivatives such as esters of thiophene compounds have been designed and synthesized as drug-like candidates with different pharmacological actions and therapeutic products. They are also widely used as important building blocks in many agrochemical products including herbicides.
US4428963 hereinafter referred to as “the’ 963 patent” discloses various thiophene intermediates for the synthesis of pharmaceutical compounds which are useful as anti-obesity and blood lipid lowering agents and can also be useful for treating atherosclerosis and related cardiovascular diseases. US7923571, hereinafter referred to as “the’571 patent” describes a process for preparing substituted 4-alkoxycarbonyl-3 -aminothiophenes which are known as intermediates, having below general formula, for preparing agrochemical active ingredients especially for substituted, herbicidally active thienyl aminocarbonyl triazolinones, disclosed in WO 01/05788, such as below, wherein Qi and Q2 are oxygen ; R1, R2 and R4 is CH3 and R3 is -OCH3.
Substituted 4-alkoxycarbonyl-3-aminothiophenes are prepared from alkoxycarbonyl-3 -thiophenes which can be prepared from dialkyl mercapto esters.
The’963 patent discloses preparation of Methyl 2-[(3-methoxy-3-oxopropyl) sulfanyl] propanoate from ethyl-2-bromopropionate as a starting material. The product obtained in the’963 is then further cyclised to get methyl 5-methyl-4- oxotetrahydrothiophene-3-carboxylate, which is another intermediate compound used for the synthesis of pharmaceutically and agrochemically active compounds. However, inventors of the present invention have observed that, when ethyl-2- bromopropionate is reacted with methyl-3 -mercaptopropionate as described in the‘963 patent, it leads to the formation of a mixture of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate and Ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate, which on cyclisation, gives a mixture of 3-Methyl 5-methyl- tetrahydrothiophene carboxylate intermediate (desired intermediate- around 75 %) and ‘3-Ethyl-5- methyl-tetrahydrothiophene carboxylate intermediate (un-desired intermediate around 25 % of the total mixture). This mixture of intermediates, specifically when employed for the preparation of thiencarbazone-methyl, and the mixture of intermediate compounds in the subsequent reactions which are similar to the desired intermediate leads to formation of a mixture of end products, impacting the overall yield of the process and also the purity of the products, making the process uneconomical and industrially less feasible. This may also lead to difficulty in purifying the final product due to structural similarity.
Therefore, there is a need for a process for preparing thiophene compounds which can solve the above stated problems associated in the art. The inventors of the present invention have developed a novel process, wherein the formation of the mixture of thiophene intermediate compounds have been avoided by using alternate raw materials, which are inexpensive and use of which helps to avoid the formation of undesired products compared to the processes disclosed in the prior art, thereby making the process clean, efficient and industrially viable. Object of the invention
It is an object of the present invention is to provide a process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I).
Formula (I) Yet another object of the present invention is to provide Thiencarbazone-methyl of Formula (II), prepared from the compound of Formula (I) of the present invention. It is another object of the present invention to provide a clean, efficient and industrially viable process for the preparation of thiophene compounds.
Summary of the invention
In an aspect of the present invention, there is provided a process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising, reacting compound of Formula (III),
Formula (III) with methyl-3 -mercaptopropionate of Formula (IV) in presence of a base,
Formula (IV) wherein Lg is a leaving group selected from -X (halogen atom), o-mesylate group, or o-tosylate group.
Another aspect of the present invention is to provide a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising: reacting compound of Formula (III) with methyl-3-mercaptopropionate of Formula (IV) in presence of a base, Formula (III)
Formula (IV) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group; and, wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
Formula (V)
Another aspect of the present invention is to provide compound of Formula (V) substantially free from, Ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
Another aspect of the present invention is to provide a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising the steps of: i. reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula (IV) in presence of a base,
Formula (III) Formula (IV) to give Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V). Formula (V) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group, ii. treating said compound of Formula (V) of step i) with base to form methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula
(I),
Yet another aspect of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II),
Formula (II) wherein the process comprises, reacting compound of formula (III),
Formula (III) with methyl-3-mercaptopropionate of Formula (IV), in presence of a base,
Formula (IV) to obtain Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula
(I),
Formula (I) wherein Lg is a leaving group selected from X (halogen), o-mesylate, o-tosylate; and converting Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) to thiencarbazone-methyl of Formula (II).
Yet another aspect of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II),
Formula (II) wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
Formula (V)
Detailed Description of the invention: In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as commonly understood by the person of ordinary skill in the art to which this invention pertains.
As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The term ‘impurities’ refers to one or more unreacted synthetic intermediates, reagents, solvents, organic and/or inorganic products of side reactions, organic and/or inorganic salts and/or other undesired materials.
The term “substantially free from impurities” refers to Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V); Methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I) or Thiencarbazone methyl of Formula (II) containing less than about 3.0 % or less than about 2.0 % or less than about 1.0 % of one or more impurities.
The term “room temperature” unless stated otherwise, refers to the temperature in the range of 20°C to 35°C.
Accordingly, the present invention is now described in connection with certain embodiments of the invention which will be apparent to the person skilled in the art from the examples provided herewith.
In an embodiment, the present invention provides a process for the preparation of Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), Formula (I) comprising; reacting compound of Formula (III)
Formula (III) with methyl-3 -mercaptopropionate of Formula (IV), in presence of a base,
Formula (IV), wherein Lg is a leaving group selected from -X (Halogen atom), o-mesylate group or o-tosylate group.
In an embodiment, the compound of Formula (III) is selected from methyl 2- bromopropanoate, methyl-2-chloropropanoate, Methyl-2-(methanesulfonyloxy) propanoate, or Methyl 2-[(4-tolylsulfonyl)oxy]propionate.
In an embodiment, the compound of Formula (III) is methyl-2-chloropropanoate.
In an embodiment, the base used for the reaction is selected from the group comprising alkali metal alkoxide or alkaline earth metal alkoxide or the mixture thereof.
In another embodiment, the base used for reacting the compound of Formula (III) with methyl-3 -mercaptopropionate of Formula (IV) is selected from alkali metal carbonates, hydrides, alkoxide of hydroxides, such as sodium, potassium and lithium hydroxide, and the alkaline earth metal hydroxides, such as barium, calcium and magnesium hydroxide or organic bases including but not limited to amines, cyclic, acyclic or caged, alone or as a mixture with bases prepared from alkali metals; the preferred base is alkali metal alkoxide , such as sodium methoxide.
In another embodiment, the base used for reacting compound of Formula (III) with methyl-3-mercaptopropionate of Formula (IV) is 1.0 to 2.0 equivalent with respect to the compound of Formula (III), preferably 1.0 to 1.5 equivalent of base is used.
In another embodiment, the reaction of compound of Formula (III) with compound of Formula (IV) is carried out in a solvent selected from alkanols which are straight or branched chain alcohols having 1-20 carbon atoms, preferably lower alkanols having 1-6 carbon atoms such as methanol, ethanol, propanol, isopropanol, more preferably methanol is used as a solvent.
In an embodiment, the reaction is carried out in an alkanol solvent selected from the group comprising of methanol, ethanol, propanol, isopropanol or mixture thereof.
In yet another embodiment, the reaction of compound of Formula (III) with compound of Formula (IV) is carried out at about -5°C to about 10°C.
In an embodimentthe reaction is carried out at about 0°C to about 5 °C.
In an embodiment, the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I)
Comprising the steps of: reacting compound of Formula (III) with methyl-3-mercaptopropionate of Formula (IV) in presence of base,
Formula (III) Formula (IV) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group; and, wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
Formula (V)
In accordance with above embodiment, the reaction is carried out with or without isolating Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V).
In an embodiment of the present invention, methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) or Methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), prepared according to the present invention is substantially free from impurities.
In an embodiment of the present invention, methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) or Methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), prepared according to the present invention is substantially free from impurities, wherein the said impurities are ethyl 2-[(3- methoxy-3-oxopropyl)thio]propanoate, Methyltetrahydro-5-Ethyl-4-oxo-3- thiophenecarboxylate or mixture thereof.
In an embodiment, there is provided methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V), substantially free from ethyl 2-[(3- methoxy-3-oxopropyl)thio]propanoate.
In an embodiment, there is provided methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V), containing about less than 3 % of ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
In an embodiment, there is provided methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V), containing about less than 2 % of ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
In an embodiment, there is provided methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V), containing about less than 1 % of ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
In yet another embodiment the present invention provides the process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising: reacting methyl-2-chloropropanoate of Formula (Illa)
Formula (Illa) with methyl-3 -mercaptopropionate of Formula (IV), in presence of a base,
Formula (IV)
In another embodiment, the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising: reacting methyl-2-chloropropanoate of Formula (Illa) with methyl-3- mercaptopropionate of Formula (IV), in presence of a base, Formula (Illa)
Formula (IV) wherein the process proceeds via the formation Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V),
Formula (V)
In another embodiment, the present invention provides a process for preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) comprising the steps of : i. reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula (IV) in presence of a base,
Formula (III) Formula (IV) to give Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V);
Formula (V) wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group; ii. treating step i) compound with base to form methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate of Formula (I).
In accordance with the above embodiment, methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) of step i) is isolated after completion of the reaction.
In an embodiment, step ii) of the process is carried out with or without isolating compound of Formula (V).
In an embodiment, the compound, methyl 2-[(3-methoxy-3-oxopropyl)thio] propanoate of Formula (V) of step i) is isolated and used for preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I).
In an embodiment, the compound methyl 2-[(3-methoxy-3-oxopropyl)thio] propanoate of Formula (V) of step i) is not isolated and taken for further reaction.
In an embodiment, step ii) is carried out in presence of base selected from the group comprising alkali metal alkoxide or alkaline earth metal alkoxide or the mixture thereof.
In an embodiment, methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V) is treated with a base in a solvent to obtain methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I). In an embodiment, the base used in step ii) for treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) is selected from alkoxide of alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkoxide of alkaline earth metal hydroxides, such as barium hydroxide, calcium hydroxide and magnesium hydroxide; or organic bases including but not limited to amines, cyclic, acyclic or caged, alone or as a mixture with bases prepared from alkali metals; the preferred base is alkali metal alkoxide, such as sodium methoxide.
In another embodiment, the alkoxide of alkali metal hydroxides or alkaline earth metal hydroxides used for treating methyl 2-[(3-methoxy-3-oxopropyl) thio]propanoate of Formula (V) to get methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I) is 0.95 to 3.0 equivalent; preferably 1.0 to 2.0 equivalent is used.
In another embodiment, step ii) of the reaction is carried out in a solvent selected from aliphatic or aromatic hydrocarbons; aliphatic or aromatic halogenated hydrocarbons.
In an embodiment, the solvent used for treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) to get Methyl tetrahydro-5-methyl-4- oxo-3-thiophenecarboxylate of Formula (I) is selected from, aliphatic hydrocarbons such as pentane, n-hexane, n-heptane or aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform or aromatic hydrocarbons such as benzene, toluene, xylene, halogenated aromatic hydrocarbons such as monochlorobenzene, dichlorobenzene, and the like. The preferred solvent is an aromatic hydrocarbon, such as toluene.
In yet another embodiment, step ii) reaction of treating methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V) to get methyl tetrahydro-5-methyl-4- oxo-3-thiophenecarboxylate of Formula (I) is carried out at a temperature in the range from about 25 °C to about 100°C. In yet another embodiment step ii) reaction is carried out in the range of about 50°C to about 80°C.
In yet another embodiment, the reaction is carried out for a period from 6 to 10 hours, preferably 6 to 8 hours.
In an embodiment, the present invention provides a process for the preparation of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), wherein the process proceeds via preparation of methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
In an embodiment, there is provided methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V), substantially free from undesired impurity Ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate.
In an embodiment, the present invention provides a process for the preparation of thiencarbazone-methyl of Formula (II) comprising; a) preparing methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V), substantially free from undesired impurity Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate; b) preparing methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) using methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V), substantially free from undesired impurity Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate; and c) converting methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) to thiencarbazone-methyl of Formula (II).
In an embodiment, the present invention provides a process of preparing thiencarbazone-methyl of Formula (II),
Formula (II) comprising: reacting compound of Formula (III), with methyl-3-mercaptopropionate of Formula
(IV) in presence of a base, Formula (III)
Formula (IV) to get methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I),
Formula (I) wherein Lg is a leaving group selected from X (halogen), o-mesylate, o-tosylate; and converting methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula
(I) to Thiencarbazone-methyl of Formula (II).
In an embodiment, the present invention provides the process of preparing thiencarbazone-methyl of Formula (II),
Formula (II) comprising reacting methyl-2-chloropropanoate of formula (Illa) with methyl-3- mercaptopropionate of Formula (IV) in presence of a base to get Methyl tetrahydro- 5-methyl-4-oxo-3 -thiophenecarboxylate of Formula (I) and
Formula (Illa) Formula (IV) Formula (I) converting Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I), to thiencarbazone-methyl of Formula (II).
In accordance with the above embodiment, the conversion of methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate of Formula (I) to thiencarbazone-methyl of Formula (II) is carried out via processes known by the skilled person. In accordance with the above embodiment, the conversion of methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate of Formula (I), to thiencarbazone-methyl of Formula (II) is carried out by a process comprising the steps of: i) converting compound of Formula (I) to compound of Formula (VI) under heating,
ii) converting compound of Formula (VI) to compound of Formula (VII)
Formula (VII) iii) reacting compound of Formula (VII) with compound of Formula (VIII), to obtain thiencarbazone-methyl of Formula (II).
Yet another embodiment of the present invention is to provide a process of preparing Thiencarbazone-methyl of Formula (II), Formula (II) wherein the process proceeds via the formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
Formula (V)
In an embodiment of the present invention, Thiencarbazone methyl of Formula (II), prepared according to the present invention is substantially free from impurities.
In an embodiment of the present invention, Thiencarbazone methyl of Formula (II), prepared according to the present invention is substantially free from impurities, wherein the said impurities are ethyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate, Methyl tetrahydro-5-Ethyl-4-oxo-3-thiophenecarboxylate or mixture thereof.
In an embodiment of the present invention, Thiencarbazone methyl of Formula (II), prepared according to the present invention contains less than about 3.0 % ethyl 2- [(3-methoxy-3-oxopropyl)thio]propanoate, methyl tetrahydro-5-Ethyl-4-oxo-3- thiophenecarboxylate or mixture thereof.
Advantages of the present invention
1. The present process is simple, efficient and enables production on an industrial scale.
2. The present process provides the intermediate and desired compounds in good yield and high purity. 3. The present invention provides highly pure methyl tetrahydro-5-methyl-4-oxo- 3 -thiophenecarboxylate of Formula (I), significantly substantially free from impurities.
EXAMPLES
The embodiments of the present invention are illustrated by below given examples. However, the scope of the present invention is not to be construed as limited by the examples.
Example 1:
Preparation of Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I):
Sodium methoxide (1.02 kg) in toluene (29 L) was charged into the reactor. Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate (3 kg; 14.544 moles) of Formula (V) was added to the above sodium methoxide solution at 35°C to 40°C dropwise in 5 hours. The reaction mass was heated to 65°C to 70°C and maintained at this temperature for 4 to 6 hours. The reaction mixture was then cooled to room temperature and water (17L) was added to the reaction mass. Layers were separated. The aqueous layer was cooled and acidified with 10% aqueous hydrochloric acid (6.9 L), with the addition of dichloromethane (9L). The layers were separated, and dichloromethane from the organic layer was evaporated to get the title compound (2.110 kg).
Methyl tetrahydro-5-Ethyl-4-oxo-3 -thiophenecarboxylate (Impurity): Not detected.
Example 2
Preparation of Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) according to patent US4428963: a) Preparation of Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V): Methyl-3 -Mercapto propionate (132.58 g 1.1 moles) was charged in methanol (100 ml) to make a solution. The reaction mixture was cooled to 0°C to 5 °C and added 25 % methanolic solution of sodium methoxide solution (240 ml). To the reaction mixture was added ethyl-2-bromopropionate (200 g; 1.1 moles) as a solution in methanol (200 ml). The reaction mixture was allowed to proceed at 25°C to 30°C overnight. The solvent was evaporated, and the residue was partitioned between ether and 10 % sodium bicarbonate. The aqueous phase was further extracted with ether. The combined organic extracts were dried over magnesium sulphate and evaporated to yield the title compound (243.8 g) with 93.23 % purity.
It was observed that the undesired impurity namely Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate is present in an amount of 3.65 %. b) Preparation of Methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I)
Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V) (121.4 g; 0.552 moles), as obtained in 2-a) as a solution in dry benzene (90 ml ) was added to dropwise to a suspension of anhydrous sodium methoxide (30 g) in dry benzene (200 ml). The reaction was allowed to proceed overnight. The mixture was partitioned between water and ether. The aqueous phase was then acidified to pH 1 with 6 N HC1 and extracted three times with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate, and evaporated to get 79.17 g of mixture of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-5-Ethyl-4-oxo-3 -thiophenecarboxylate as a colorless oil (in a ratio of 79:21). Methyl tetrahydro-5-Ethyl-4-oxo-3-thiophenecarboxylate (Impurity): 18. 11 %. Following table summarizes the results of above examples:
From the above table it is evident that the process of the present invention as exemplified in example 1 provides the compound of formula (I) devoid of an impurity namely “Methyl tetrahydro-5-Ethyl-4-oxo-3-thiophenecarboxylate” as against example 2, having 18.11 % of methyl tetrahydro-5-Ethyl-4-oxo-3- thiophenecarboxylate.
Example 3
Preparation of Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate of Formula (V)
Methyl-3 -Mercapto propionate (7 kg; 50 moles) in methanol (7 L) was charged to the reactor and 30 % methanolic solution of sodium methoxide (10.320 kg) was added to it in 3 to 4 hours at room temperature. Stirred the reaction mass at this temperature for 1 hour. To the reaction mixture was added methyl-2- chloropropionate (7.110 kg; 58.017 moles) as a solution in methanol (4.67 L) at 0°C to 5 °C in 4 hours and continued stirring at this temperature for 1 hour. Methanol was distilled out under vacuum. To the residual mass thus obtained was added dichloromethane and water to make clear solution at 20°C to 25 °C. The layers were separated, solvent was distilled out to get the title compound (11.98 kg) as an oily product. (Yield: 99.7% and purity 95.7%).
The analysis of product obtained showed absence of undesired Ethyl 2-[(3- methoxy-3-oxopropyl)thio]propanoate. Example 4:
Preparation of Thiencarbazone-methyl of Formula (II): i. Preparation of methyl 4-amino-5-methylthiophene-3-carboxylate hydrochloride:
Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate of Formula (I) (10 kg; 45.9 moles) as obtained by process of example-1, acetonitrile (19 L), and hydroxyl amine hydrochloride (4.8 kg; 67.69 moles) were charged. The reaction mass was heated to 80-85°C for 7 hours under stirring. The reaction mass was cooled to 20- 25°C and the suspension was filtered, the wet cake was washed with pre-cooled water twice. The wet cake was dried to obtain 9.5 kg of title product as white solid. ii. Preparation of methyl 5-methyl-4-sulfamoylthiophene-3-carboxylate:
To a solution of 30 % hydrochloric acid (3.690 kg) with water (3.990 kg), was added 3-amino-4-carboxy-2-methylthiophene hydrochloride (2.5 kg; 10.68 moles). The resultant suspension was cooled to -5 to -10°C. To this reaction mass, solution of -34% aqueous sodium nitrite (2.5 kg) was dropwise added within 2 hours & the reaction mass was maintained under stirring for 2 hours to get the diazotized reaction mass. In another reaction vessel, sodium bisulfite (3.1 kg) was added to dichloromethane and cooled to -5 to -10°C, 30% hydrochloric acid (3.850 kg) was added to the suspension of sodium bisulfite in dichloromethane at -5 to -10°C in 2 hours and the mass was maintained for an additional 2 hours. The reaction temperature of above mass was raised to 15-20°C and to this was added copper (I) chloride (50 g) followed by addition of dodecyl trimethyl ammonium bromide (50g). To this solution was added previously prepared diazotized reaction mass lot wise in 30-45 min at 15-20°C. The reaction mass was stirred for Ihour at 15-20°C and then at 25-30°C for 7 hours. The separated aqueous phase was re-extracted with dichloromethane. The oraganic layers were combined and -30 % dichloromethane was recovered by distillation at 40-50°C. The organic layer was cooled to 15-20°C and ammonium carbonate (1.9 kg) was added to this in portion wise within 1-2 hours. The reaction mass was stirred for 6 hours. After completion of the reaction, the reaction mass was diluted with water. The layers were separated, the aqueous layer was re-extracted with dichloromethane. The combined organic layer was concentrated to get 1.2 kg yellowish title compound (Purity: 96.68 %) iii. Preparation of Thiencarbazone-methyl: Charged acetonitrile (765 ml) with methyl 5 -methyl-4- sulfamoylthiophene-3 - carboxylate (70 g; 0.293 moles), phenyl 4,5-dihydro-3-methoxy-4-methyl-5-oxo- lH-l,2,4-triazole-l-carboxylate (73 g; 0.293 moles) and l,8-diazabicyclo-5.4.0- undec-7-ene (DBU) (44.5 g; 0.293 moles) at 25°C to 30°C to the reactor. The reaction mixture was stirred for 6 to 8 hours. Excess acetonitrile was distilled out to get desired product as a crude mass. To the crude mass, dichloromethane and water was added and stirred for 15 minutes. The layers were separated, and organic layer was washed with IN HC1 solution followed by water wash. The solvent was evaporated from the organic layer to get Thiencarbazone-methyl. The crude Thiencarbazone-methyl was crystalized from isopropanol to get 60 g of pure Thiencarbazone-methyl (Purity: 98.16 %).

Claims

CLAIMS:
1. A process for the preparation of methyl-tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate of Formula (I),
Formula (I) comprising: reacting compound of Formula (III) with methyl-3-mercaptopropionate of
Formula (IV) in presence of a base,
Formula (III) Formula (IV ) wherein Lg is a leaving group selected from -X (halogen atom), o-mesylate group, or o-tosylate group, and wherein the process proceeds via formation of Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate of Formula (V).
Formula (V)
2. The process as claimed in claim 1, wherein the base is selected from the group comprising of alkali metal alkoxide, alkaline earth metal alkoxide.
3. The process as claimed in claim 1, wherein the reaction of compound of formula (III) and formula (IV) is carried out at a temperature ranging from about -5 °C to about 10°C.
4. The process as claimed in claim 1, wherein the reaction is carried out in an alkanol solvent selected from the group comprising of methanol, ethanol, propanol, isopropanol or a mixture thereof.
5. The process as claimed in claim 1, wherein said compound of Formula (V) is substantially free from Ethyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate.
6. The process as claimed in claim 1, wherein the reaction is carried out with or without isolating said compound of Formula (V).
7. A compound of Formula (V), substantially free from Ethyl 2-[(3-methoxy- 3-oxopropyl)thio]propanoate.
8. A process for preparing methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate, comprising: reacting methyl-2-chloropropanoate of Formula (Illa) with methyl-3- mercaptopropionate in presence of a base,
Formula (Illa) wherein the process proceeds via the formation Methyl 2-[(3-methoxy-3- oxopropyl)thio]propanoate.
9. A process for preparing methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate comprising the steps of : i. reacting compound of Formula (III), with methyl-3-mercaptopropionate
Formula (III), to give Methyl 2-[(3-methoxy-3-oxopropyl)thio]propanoate; wherein Lg is a leaving group selected from -X(halogen atom), o-mesylate group, or o-tosylate group; ii. treating step i) compound with base to form methyl tetrahydro-5- methyl-4-oxo-3-thiophenecarboxylate.
10. The process as claimed in claim 9, wherein step ii) is carried out in presence of base selected from the group comprising of alkali metal alkoxide, alkaline earth metal alkoxide.
11. The process as claimed in claim 9, wherein step ii) is carried out at a temperature ranging from about 25°C to about 100°C.
12. The process as claimed in claim 9, wherein step ii) is carried out in a solvent selected from aliphatic or aromatic hydrocarbons; aliphatic or aromatic halogenated hydrocarbons.
13. A process of preparing thiencarbazone-methyl, comprising: reacting compound of Formula (III), with methyl-3-mercaptopropionate in presence of a base,
Formula (III) to get methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate, wherein Lg is a leaving group selected from X (halogen), o-mesylate, o- tosylate; and converting methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate to Thiencarbazone-methyl.
14. A process of preparing Thiencarbazone-methyl, comprising: reacting methyl-2-chloropropanoate with methyl-3-mercaptopropionate in presence of a base to get Methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate and converting Methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate to thiencarbazone-methyl.
15. The process as claimed in claim 14, wherein conversion of methyl tetrahydro-5-methyl-4-oxo-3-thiophenecarboxylate to thiencarbazone- methyl is carried out by a process comprising the steps of: i. converting methyl tetrahydro-5-methyl-4-oxo-3- thiophenecarboxylate to compound of Formula (VI) under the heating,
ii. converting compound of Formula (VI) to compound of Formula
(VII), iii. reacting compound of Formula (VII) with compound of Formula
(VIII) to obtain thiencarbazone-methyl.
PCT/IB2025/055302 2024-05-25 2025-05-22 Process for the preparation of thiophene compounds Pending WO2025248390A1 (en)

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