WO2026035749A1 - Procédés associés à la formation de n-éthyl-2-(pyridin-3-yl)thiazol-5-amine - Google Patents

Procédés associés à la formation de n-éthyl-2-(pyridin-3-yl)thiazol-5-amine

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Publication number
WO2026035749A1
WO2026035749A1 PCT/US2025/040751 US2025040751W WO2026035749A1 WO 2026035749 A1 WO2026035749 A1 WO 2026035749A1 US 2025040751 W US2025040751 W US 2025040751W WO 2026035749 A1 WO2026035749 A1 WO 2026035749A1
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WIPO (PCT)
Prior art keywords
process according
acid
moles
mmol
equiv
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/US2025/040751
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English (en)
Inventor
Nakyen Choy
Daniel Kohlman
Fangzheng LI
Jeffrey Scott Nissen
Aditya Patil
Neeraj Sane
Abraham D. SCHUITMAN
Zican SHEN
Chunming Zhang
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.)
Corteva Agriscience LLC
Original Assignee
Corteva Agriscience LLC
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Application filed by Corteva Agriscience LLC filed Critical Corteva Agriscience LLC
Publication of WO2026035749A1 publication Critical patent/WO2026035749A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Processes to make and use a molecule of S3 are provided. Additionally, processes related to the formation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4) or salts thereof are provided. Examples of salts include the salts of methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, and phosphoric acid.
  • the molecule S3 may be useful in the process to prepare V-(4-chloro-2-(pyri din-3 -yl)thiazol-5-yl)-A- ethyl-3-(methylsulfonyl)propanamide. 212574-US-PRV-l
  • a molecule, A-(2-(ethylamino)-2-thioxoethyl)ni cotinamide (also known as “S3” herein), is provided.
  • molecule S3 may be useful in the process to prepare A-cthyl-2-(pyridin-3-yl)thiazol-5-amine (S4) or salts thereof.
  • ambient pressure refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.
  • ambient temperature or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.
  • catalyst refers to any substance that increases the rate of a reaction without itself being consumed.
  • bases are organic bases and inorganic bases.
  • organic bases are pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, 5-ethyl-2-methylpyridine, A(7V-diisopropylethylamine (“DIPEA”), N- methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, and triethylamine (“EtsN”).
  • inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), and sodium bicarbonate (“NaHCOs”). Mixtures of bases may also be used.
  • the reaction may be conducted at temperatures from about -10 °C to about 25 °C, and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.
  • thiolation reagents are sodium hydrogen sulfide or hydrate thereof, sodium sulfide, ammonium sulfide, hydrogen sulfide, and pre-formed ethylamine-hydrogen sulfide salt.
  • thiolation reagents sodium hydrogen sulfide or hydrate thereof, sodium sulfide, ammonium sulfide, hydrogen sulfide, and pre-formed ethylamine-hydrogen sulfide salt.
  • from about 1 mole to about 5 moles of thiolation reagent per mole of S2 may be used; preferably, from about 1.3 moles to about 3.5 moles of thiolation reagent per mole of S2 may be used.
  • reaction in Scheme Two is conducted in the presence of ethylamine or a salt thereof.
  • a salt is the hydrochloride salt, ethanamine hydrochloride.
  • from about 1 mole to about 5 moles of ethylamine or ethanamine hydrochloride per mole of S2 may be used; preferably, from about 1.3 moles to about 3.5 moles of ethylamine or ethanamine hydrochloride per mole of S2 may be used.
  • the reaction in Scheme Two is conducted in the presence of a polar aprotic or a polar protic solvent.
  • polar aprotic solvents are tetrahydrofuran (“THF”), acetonitrile, chlorobenzene (“PhQ”), and dichloromethane (“DCM”).
  • polar protic solvents are methanol (“MeOH”), ethanol (“EtOH”), isopropyl alcohol (z-PrOH), and water.
  • mixtures of solvents may be used.
  • reaction in Scheme Two may be conducted at temperatures from about 0 °C to about 50 °C and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.
  • Lewis or Bron st ed acids examples include sulfuric acid (“H2SO4”), fuming sulfuric acid (“H2SO4 + SO3”), phosphorus trichloride (“PCI3”), phosphorus oxychloride (“POCI3”), polyphosphoric acid, methanesulfonic acid (“MsOH”), trifluoromethanesulfonic acid (“TfOH”), anhydrous /2-toluenesulfonic acid, and benzenesulfonic acid.
  • MsOH methanesulfonic acid
  • TfOH trifluoromethanesulfonic acid
  • anhydrous /2-toluenesulfonic acid anhydrous /2-toluenesulfonic acid
  • benzenesulfonic acid In general, from about 1.5 moles to about 25 moles of Lewis or Bronsted acid per mole of S3 may be used; preferably, from about 2.5 moles to about 15 moles of Lewis or Bronsted acid
  • the reactions in Scheme One through Scheme 3 may be done as a telescope process.
  • reaction mixture was heated to 30 °C. After stirring overnight, the mixture was used as is in the next step.
  • nicotinic acid 13.00 g, 1.0 equiv, 105.6 mmol
  • piperidine-l-carbaldehyde 59.75 mg, 0.0050 equiv, 0.5280 mmol
  • DCM dichloromethane
  • Oxalyl dichloride 14.07 g, 1.050 equiv, 110.9 mmol was added dropwise via syringe. The temperature was controlled below 20 °C using a water bath.
  • Ethanamine hydrochloride (EtNEb’HCl, 25.8 g, 3 equiv, 317 mmol) was added followed immediately by sodium sulfide (12.4 g, 1.5 equiv, 158 mmol). The stirred mixture was heated to 40 °C. After 24 hours, the mixture was filtered, concentrated, and diluted with THF to provide S3 as a THF solution.
  • reaction mixture was diluted dropwise with water (5 mL).
  • KOH potassium hydroxide
  • This mixture was warmed to 70 °C, at which point all the solid dissolved, and the layers were separated.
  • the organic layer was diluted with ethyl acetate (EtOAc, 20 mL) and washed with water (5 mL).
  • the slurry was heated to 60 °C for 30 minutes, and to this mixture was added sulfuric acid (16.97 g, 9.22 mL, 4.0 equiv, 173.0 mmol) dropwise over 15 minutes. The mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to 25 °C and diluted slowly with water (50 mL) while maintaining the internal temperature ⁇ 25 °C. The resulting mixture was diluted with EtOAc (30 mL). The aqueous layer was separated and was neutralized with 10 N KOH added dropwise to maintain the temperature ⁇ 36 °C, resulting in a tan solid.
  • Step 1 To a 20 mL vial, A-(cyanomethyl)nicotinamide (S2, 1.5 g, 1 equiv, 9.31 mmol) and ammonium sulfide (1.65 g, 1.3 equiv, 12.1 mmol, 50 wt% aqueous solution) were added. Methanol (9 mL) was added to solubilize all the solids. The reaction mixture was stirred at 40 °C for 16 hours. The product precipitated out of the solution.
  • A-(cyanomethyl)nicotinamide S2, 1.5 g, 1 equiv, 9.31 mmol
  • ammonium sulfide (1.65 g, 1.3 equiv, 12.1 mmol, 50 wt% aqueous solution
  • Step 2 To a 20 mL vial, ethanamine (83.1 mg, 0.92 mL, 2.00 molar in THF, 1.2 equiv, 1.84 mmol) was added. The vial temperature was set at 5 °C. Hydrogen sulfide (62.8 mg, 2.36 mL, 0.80 molar in THF, 1.2 equiv, 1.84 mmol) was added to the vial in a controlled manner to form ethanamine-hydrogen sulfide salt solution. A-(2-Amino-2-thioxoethyl)nicotinamide (300 mg, 1.54 mmol) and methanol (1 mL) were added to form a homogeneous solution.
  • the reaction mixture was heated to 60 °C over 15 minutes and was kept stirring at 60 °C until the reaction was complete (in 2 to 4 hours as monitored by 'H NMR spectroscopy or UPLC).
  • the resulting mixture was allowed to cool to ambient temperature (20 °C) and diluted with deionized water (40 mL). After cooling to 0-5 °C, 50 wt% NaOH was added dropwise to adjust the pH to 9-10.
  • the desired product, S4, precipitated was collected by filtration with rinsing with deionized water (5 mL), and was dried in a vacuum oven at 50 °C and 1-10 mmHg overnight. Yields ranged from 1.77 g to 1.91 g (86- 93%). Analytical data were consistent with reference.
  • V-(2-(Ethylamino)-2-thioxoethyl)nicotinamide (S3, 4.46 g, 20 mmol) was added to methanesulfonic acid (MsOH, 28.83 g, 300 mmol, 15 equiv) at 20 °C in a 50-mL three-neck 212574-US-PRV-l round bottom flask equipped with a condenser, a thermocouple, a magnetic stirrer, and a nitrogen blanket. An exothermic reaction occurred where the temperature increased from 20 °C to 42 °C in 10 minutes, forming a light brown solution.
  • MsOH methanesulfonic acid
  • A-(2-(Ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.00 g, 1 equiv, 4.48 mmol) and trichloroacetic acid (6.00 mL) were added to a round bottom flask with magnetic stirring.
  • Trichloroacetic acid was a solid at ambient temperature.
  • the resulting mixture was warmed slowly to 80 °C and the mixture became homogeneous.
  • the resulting solution was then treated dropwise with fuming sulfuric acid (1.32 g, 716 pL, 3 equiv, 13.4 mmol) over 10 minutes to provide a yellow/orange solution.
  • reaction was determined to be complete after being stirred for 1 hour at 80 °C.
  • the reaction mixture was cooled to ambient temperature and stored overnight, during which time the mixture solidified and a tan solid was obtained.
  • the reaction mixture was dissolved in water (20 mL) and the resulting solution was 212574-US-PRV-l
  • a process for the preparation of a molecule according to ID the process comprising: reacting
  • a process for the preparation of a molecule according to ID the process further comprising: reacting a. S1 , wherein X 1 is OH (Sla) or Cl (Sib) or a hydrochloride salt thereof (*HC1, Slb-HCl); and b. 2-aminoacetonitrile or 2-aminoacetonitrile hydrochloride in the presence of a base and a solvent to provide S2 or S2-HC1.
  • 26D The process according to 25D, wherein the carboxylic acid activator is thionyl chloride, oxalyl chloride, and pivaloyl chloride. 212574-US-PRV-l
  • 29D The process according to any one of 25D-28D, wherein the base is an organic base.
  • organic base is selected from pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, 5-ethyl-2-methylpyridine, A,A-diisopropylethylamine (“DIPEA”), N- methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, triethylamine (“EtsN”), or mixtures thereof.
  • DIPEA A,A-diisopropylethylamine
  • NMI N- methylimidazole
  • NMM A-methylmorpholine
  • EtsN triethylamine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne une molécule, N-(2-(éthylamino)-2-thioxoéthyl)nicotinamide (S3), ayant la formule suivante. L'invention concerne également des procédés de fabrication et d'utilisation d'une molécule de S3.
PCT/US2025/040751 2024-08-07 2025-08-05 Procédés associés à la formation de n-éthyl-2-(pyridin-3-yl)thiazol-5-amine Pending WO2026035749A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463680256P 2024-08-07 2024-08-07
US63/680,256 2024-08-07

Publications (1)

Publication Number Publication Date
WO2026035749A1 true WO2026035749A1 (fr) 2026-02-12

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ID=97026445

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/040751 Pending WO2026035749A1 (fr) 2024-08-07 2025-08-05 Procédés associés à la formation de n-éthyl-2-(pyridin-3-yl)thiazol-5-amine

Country Status (1)

Country Link
WO (1) WO2026035749A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129497A1 (fr) 2009-05-05 2010-11-11 Dow Agrosciences Llc Compositions pesticides
WO2013184475A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013184476A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013184480A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013186089A2 (fr) * 2012-06-14 2013-12-19 Basf Se Procédés pesticides utilisant des composés thiazole à substitution 3-pyridyle et leurs dérivés pour lutter contre des nuisibles
WO2023015135A1 (fr) 2021-08-03 2023-02-09 Corteva Agriscience Llc Polymorphes ayant une activité pesticide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129497A1 (fr) 2009-05-05 2010-11-11 Dow Agrosciences Llc Compositions pesticides
WO2013184475A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013184476A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013184480A2 (fr) 2012-06-04 2013-12-12 Dow Agrosciences Llc Procédés de production de certains 2-(pyridine-3-yl)thiazoles
WO2013186089A2 (fr) * 2012-06-14 2013-12-19 Basf Se Procédés pesticides utilisant des composés thiazole à substitution 3-pyridyle et leurs dérivés pour lutter contre des nuisibles
WO2023015135A1 (fr) 2021-08-03 2023-02-09 Corteva Agriscience Llc Polymorphes ayant une activité pesticide

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