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EP-4739666-A1 - PROCESS FOR THE PREPARATION OF THIOPHENONES

EP4739666A1EP 4739666 A1EP4739666 A1EP 4739666A1EP-4739666-A1

Abstract

The present invention refers to a process for preparing a thiophen-3-ones by the simultaneous addition of trisubstitued ketones and sulfide or bisulfide anion, followed by the addition of a base. The application further refers to methods of obtaining active ingredients, such as dimethenamid.

Inventors

  • WANG, KAI
  • CHEN, JIANGUO
  • YACOVAN, AVIHAI
  • BAR NAHUM, ITSIK

Assignees

  • Adama Agan Ltd.

Dates

Publication Date
20260513
Application Date
20240703

Claims (13)

  1. 1. A process for preparing a compound of formula (I), wherein each of R 1 and R 2 is independently selected from the group consisting of hydrogen, Ci- C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl; the process comprising (i) reacting a sulfide or bisulfide anion with a compound of formula (II) wherein each of L 1 , L 2 and L 3 is independently selected from the group consisting of leaving groups; and R 1 and R 2 are as defined above; in the presence of a solvent system comprising an organic solvent; and (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.
  2. 2. The process according to claim 1, wherein R 1 and R 2 are each independently selected from the group consisting of Ci-Cg alkyl groups.
  3. 3. The process according to claim 2, wherein R 1 and R 2 are both methyl.
  4. 4. The process according to any of the previous claims, wherein L 1 , I and L 3 are each independently selected from chloride, bromine and iodide.
  5. 5. The process according to any of the previous claims, wherein the temperature in step (i) is maintained between -10°C and 30°C.
  6. 6. The process according to any of the previous claims, wherein the temperature in step (ii) is maintained between 30°C and 70°C.
  7. 7. The process according to any of the previous claims, wherein the pH in step (ii) is maintained between 11 and 13.
  8. 8. The process according to any of the previous claims, wherein the pH is maintained in step (ii) by addition of an alkaline or an alkaline-earth hydroxide or carbonates or bicarbonates.
  9. 9. The process according to any of the previous claims, wherein step (i) comprises step (ia) comprising the simultaneous addition of the sulfide or bisulfide anion and the compound of formula (II) over a period of between 1 minute and 24 hours, at a temperature between -10°C and 20°C; and step (ib) comprising reacting the mixture resulting from step (ia) for a period between 1 minute and 24 hours at a temperature between 0°C and 30°C.
  10. 10. The process according to any of the previous claims, wherein the sulfide or bisulfide anion is selected from the group consisting of sodium sulfide, sodium hydrogen sulfide and mixtures thereof.
  11. 11. The process according to any of the previous claims, wherein the process is a batch, a semibatch or a continuous process.
  12. 12. The process according to any of the previous claims, wherein the compound of formula (I) is further transformed into dimethenamid, including any of the enantiomers thereof.
  13. 13. A process for preparing dimethenamid that comprises preparing a compound of formula (I) as defined in claim 1 wherein R 1 and R 2 are methyl following the process defined in any of the previous claims, and then transforming said compound of formula (I) into dimethenamid.

Description

PROCESS FOR THE PREPARATION OF THIOPHENONES FIELD OF THE INVENTION The present invention relates to the field of synthesis of organic compounds, more specifically to a process for the preparation of thiophenones that are useful in the preparation of dimethenamid. BACKGROUND PRIOR ART The agrochemical industry is always in the search of more efficient processes for the preparation of its active ingredients (Als). The capability of providing economical and clean synthesis of the active ingredients is one of the key factors determining the commercialization of an active ingredient. Dimethenamid is a herbicide belonging to the group of chloroacetamides, that inhibits lipid synthesis. It is included in group 15 of the WSSA classification. It is typically applied on the soil to control a variety of broad-leaved weeds and grasses. It is a chiral molecule having two isomeric forms commonly known as M and P stereoisomers, dimethenamid-P being more biologically active. Dimethenamid-P Synthetic schemes to prepare dimethenamid typically involve constructing the thiophene ring (typically a thiophen-3-one), followed by incorporating the 2-methoxy-2-propanamine (or 2- methoxyisopropylamine), also known as MOIPA, to finalize by coupling the 2-chloroaceto moiety. One of the key steps is therefore the construction of the thiophen-3-one ring, that exists in two tautomeric forms. thiophen-3-one tautomers In the case of dimethenamid, the intermediate needed is 2,4-dimethyl-2,3-dihydrothiophen-3- one (also found in the literature as 2,4-dimethylthiophen-3-one), which can exist as a mixture with its tautomeric form 2,4-dimethyl-3-hydroxythiophenone (also known as 3-thiopheneol). US 5,703,248 discloses the preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one by reacting l,2,4-trichloro-2-methylpentan-3-one with F S/NaOH (examples 3a and 3d), NajS (example 3b), and NaHS (example 3c), as well as a continuous preparation in the presence of NaHS. The processes disclosed in the prior art are not satisfactory and yields can improve. There is therefore in the art a need to provide alternative procedures for obtaining dimethenamid and its intermediate 2,4-dimethyl-2,3-dihydrothiophen-3-one. There is a need for processes that provide 2,4-dimethyl-3-thiophenone more efficiently, for example improving yields, reducing impurities, and/or milder conditions. SUMMARY OF THE INVENTION The inventors have now realized that the order of addition of the reagents is key to obtain good yields in the reaction between l,2,4-trichloro-2-methylpentan-3-one and sulfide anions, and reduces the impurities, mainly intermolecular coupling products and polymers thereof. In the examples of US 5,703,248 the sulfide anion (H2S, NajS or NaHS) is either, added over 1,2,4- trichloro-2-methylpentan-3-one, or the order of addition is not specified. The inventors observed that the yield was limited by intermolecular coupling products which lead to dimmers, oligomer and polymeric by-products. Among other possible solutions, the inventors tested inverting the order and confirmed that adding l,2,4-trichloro-2-methylpentan-3-one over a solution of the sulfide anion does not solve the problem, and even further reduces the yield. The research done by the inventors shows however that the simultaneous addition of both compounds surprisingly improves the yield. Thus, a first aspect of the invention is a process for preparing a 2,3-dihydrothiophen-3-one compound of formula (I), wherein each of R1 and R2 is independently selected from the group consisting of hydrogen, Ci- C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl; the process comprising (i) reacting a sulfide or bisulfide anion with a compound of formula (II) wherein each of L1, L2 and L3 is independently selected from the group consisting of leaving groups; and R1 and R2 are as defined above; in the presence of a solvent system comprising an organic solvent; and (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide anion or bisulfide anion and the compound of formula (II) are added simultaneously. The inventors have found that the process increases the yield, and reduces intermolecular byproducts and oligomer/polymer formation. Also, the amount of intermediate species and byproducts is reduced, for example, the thiophenone wherein L3 still has not undergone the elimination, also referred to as L3-(l), or the thiophene with no double bonds, also referred to as 2H-(I): L3-(l) 2H-(I) wherein R1, R2 and L3 are as defined elsewhere in the present document. The compound of formula (I) encompasses the thiophen-3-one intermediate necessary for preparing dimethenamid, 2,4-dimethyl-2,3-dihydrothiophen-3-one. It is therefore a further aspect of the invention a process for preparing dimethenamid, the process comprising preparing a compound of formula (I) wherein R1 and R2 are methyl following the process defined herein, and then transforming sai