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WO2024168001A1 - Procédés associés à la formation de n-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-n-éthyl-3-(méthylsulfonyl)propanamide - Google Patents

Procédés associés à la formation de n-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-n-éthyl-3-(méthylsulfonyl)propanamide Download PDF

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Publication number
WO2024168001A1
WO2024168001A1 PCT/US2024/014736 US2024014736W WO2024168001A1 WO 2024168001 A1 WO2024168001 A1 WO 2024168001A1 US 2024014736 W US2024014736 W US 2024014736W WO 2024168001 A1 WO2024168001 A1 WO 2024168001A1
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process according
mmol
hcl
solvent
ethyl
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PCT/US2024/014736
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Inventor
Nakyen Choy
Megan CISMESIA
David J. COULING
Taxiarchis Minas GEORGIADIS
Kaitlyn C. Gray
Janelle K. KIRSCH
Daniel Kohlman
Kumar ITYALAM
Jeffrey Scott Nissen
Aditya N. PATIL
Brandon REIZMAN
Neeraj Sane
Zican SHEN
Tony K. Trullinger
Qiang Yang
Gary Alan Roth
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Corteva Agriscience Llc
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Publication of WO2024168001A1 publication Critical patent/WO2024168001A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/04—Sulfonic acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles

Definitions

  • Y-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide also known as “S6a” herein
  • Y-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide also known as “S6a” herein
  • agriculturally acceptable acid addition salts having the following formula is provided.
  • Molecule S6a has shown activity against green peach aphid (Myzus persicae i.e., 71% control at 200 parts per million (ppm)).
  • hydrochloride salt also known as “S6a-HCl” herein.
  • molecule S6a or S6a-HCl may be useful in the process to prepare /V-(4-chloro-2-(pyridin-3- yl )thiazol-5-yl )-/V-ethyl-3-(methyl sulfonyl )propanamide (S7a).
  • the reaction in Scheme One is conducted in the presence of an oxidizing agent that oxidizes 3-(methylthio)propanoic acid (also known as “Sla” herein) to 3- (methylsulfonyl)propanoic acid (also known as “Sib” herein).
  • an oxidizing agent that oxidizes 3-(methylthio)propanoic acid (also known as “Sla” herein) to 3- (methylsulfonyl)propanoic acid (also known as “Sib” herein).
  • oxidizing agents are oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peroxides, organic peracids (-OOH), and other inorganic oxidants, such as, potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSOs KHSO4 K2SO4 [CAS 70693-62-8] available from E.I. du Pont de Nemours and Company or its affiliates as OXONE®, a registered trademark of E.I. du Pont de Nemours and Company or its affiliates).
  • O2KHSOs KHSO4 K2SO4 a triple salt with the formula 2KHSOs KHSO4 K2SO4 [CAS 70693-62-8] available from E.I. du Pont de Nemours and Company or its affiliates as OXONE®, a registered trademark of E.I. du
  • oxidizing agent in general, about 2 moles to about 4 moles of oxidizing agent per mole of Sla, preferably, about 2.0 moles to about 3.0 moles of oxidizing agent per mole of Sla may be used. Mixtures of oxidizing agents may also be used.
  • polar solvents are polar aprotic solvents and polar protic solvents.
  • polar aprotic solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), dichloromethane (“DCM”), acetone, acetonitrile (“ACN”), AfA-dimethylformamidc (“DMF”), and dimethyl sulfoxide (“DMSO”).
  • polar protic solvents examples include acetic acid (“AcOH”), //-butanol (“n-BuOH”), isopropanol (“z-PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), formic acid (“HCOOH”), Zc/7-butyl alcohol (“Z-BuOH”), and water (“H2O”).
  • AcOH acetic acid
  • n-BuOH isopropanol
  • z-PrOH isopropanol
  • zz-PrOH zz-propanol
  • EtOH ethanol
  • MeOH methanol
  • HCOOH formic acid
  • H2O water
  • mixtures of such polar solvents may be used.
  • reaction in Scheme One may be conducted at ambient temperatures (about 15 °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.
  • ambient temperatures about 15 °C to about 25 °C
  • ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa).
  • higher and lower temperatures and pressures may be used.
  • Activated carboxylic acids S2a may include acid chlorides, mixed anhydrides and esters.
  • Acid chlorides may be prepared from the corresponding carboxylic acid by treatment with a dehydrating chlorinating reagent, such as oxalyl chloride or thionyl chloride.
  • Esters can be generated from the reaction of Sib with alcohols such as methanol or ethanol under acidic conditions. In general, about 1.0 moles to about 5 moles of activator per mole of Sib, more preferably, about 1.0 moles to about 1.5 moles of activator per mole of Sib may be used.
  • a catalyst may be used to promote the reaction of Sib to the activated form S2a.
  • catalysts include A f , A-dimethylformamide, A -formyl pyrrolidine, and A- formylpiperidine.
  • a f A-dimethylformamide
  • a -formyl pyrrolidine A-formyl pyrrolidine
  • A- formylpiperidine A- formylpiperidine.
  • about 0.01 to 0.5 moles of catalyst per mole of Sib more preferably, about 0.05 moles to about 0.1 moles of catalyst per mole of Sib may be used.
  • aprotic solvents are polar aprotic solvents and nonpolar aprotic solvents.
  • polar aprotic solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane (“DCM”), chloroform (“CHCI3”), acetonitrile (“ACN”), and benzonitrile (“PhCN”).
  • EtOAc ethyl acetate
  • THF tetrahydrofuran
  • 2-MeTHF 2-methyltetrahydrofuran
  • DCM dichloromethane
  • CHCI3 chloroform
  • ACN acetonitrile
  • PhCN benzonitrile
  • An example of a nonpolar aprotic solvent is and toluene (“PI1CH3”).
  • mixtures of such solvents may be used.
  • the reaction in Scheme Two may be conducted at ambient temperatures and ambient pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about 0 °C to about 100 °C may be used, temperatures from about 50 °C to about 80 °C may be used, preferably temperatures from about 20 °C to about 60 °C may be used.
  • the compound S2a may be isolated and used or used directly without isolation in the subsequent reaction.
  • reaction in Scheme Three may provide either the amine (S4a) or the amine hydrochloride (S4a-HCl).
  • the product of Scheme Three may be prepared as the free amine (S4a) in one step from methyl or ethyl glycinate hydrochloride (also known as “S3/3a” herein) by the reaction shown in Scheme Three in the presence of ethylamine and a secondary base.
  • secondary bases are organic bases and inorganic bases.
  • organic bases are N,N- diisopropylethylamine (“DIPEA”) and triethylamine (“TEA”).
  • inorganic bases examples include potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCCh”), and sodium hydroxide (“NaOH”).
  • the secondary base can be added after the reaction is complete.
  • about 1 mole to about 15 moles of ethylamine per mole of S3/3a may be used; more preferably, about 5 moles to about 12 moles of ethylamine per mole of S3/3a may be used.
  • about 0.8 moles to about 2 moles of secondary base per mole of S3/3a may be used; more preferably, about 0.8 to about 1.2 moles of secondary base per mole of S3/3a may be used.
  • reaction in Scheme Three is conducted in the presence of a polar or a nonpolar solvent.
  • polar solvents are polar aprotic solvents and polar protic solvents.
  • polar aprotic solvents are tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2- MeTHF”), anisole, and acetonitrile (“ACN”).
  • polar protic solvents are //-butanol (“n-BuOH”), sec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z-PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”).
  • a nonpolar solvent is toluene (“PhCHs”).
  • PhCHs toluene
  • mixtures of such solvents may be used. Water is preferred.
  • the reaction in Scheme Three may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -20 °C to about 50 °C may be used; preferably temperatures from about -10 °C to 10 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.
  • kPa kilopascal
  • amine S4a may be isolated as a solution in the reaction solvent.
  • S4a may be isolated as a 5-40 weight percent (wt%) solution in acetonitrile, water, or sec- butanol.
  • reaction in Scheme Three to produce amine S4a may be conducted under flow conditions.
  • Flow conditions are known in the art. See for example Luis, Santiago V., and Eduardo Gar ci a- Verdugo, eds. Chemical reactions and processes underflow conditions. No. 5. Royal Society of Chemistry, 2010.
  • S4a may be converted to the hydrochloride (HC1) salt (S4a-HCl) by treatment with anhydrous HC1 or aqueous HC1, subsequent to the reaction with ethylamine.
  • HC1 salt S4a-HCl
  • S4a-HCl hydrochloride
  • HC1 salt form is conducted in the presence of a polar solvent.
  • polar solvents are polar aprotic solvents and polar protic solvents.
  • polar aprotic solvents examples include 1,4-di oxane, ethyl acetate (“EtOAc”), methyl Ze/7-butyl ether (“MTBE”), and cyclopentyl methyl ether (“CPME”).
  • polar protic solvents examples include ec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”).
  • s-BuOH 4-methyl-2-pentanol
  • MIBC 4-methyl-2-pentanol
  • z-PrOH isopropanol
  • EtOH ethanol
  • MeOH methanol
  • H2O water
  • mixtures of such polar solvents with each other or with nonpolar solvents such as toluene may be used.
  • 3-pyridinecarboxaldehyde also known as nicotinaldehyde, a Bronsted base, and sulfur.
  • 3-pyridinecarboxaldehyde also known as nicotinaldehyde, a Bronsted base, and sulfur.
  • about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used; more preferably, about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used.
  • Commercially available forms of 3-pyridinecarboxaldehyde include the neat form or as an aqueous solution, both of which can be used.
  • about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used.
  • about 0.05 mole to about 5 moles of Bronsted base per mole of S4a or S4a-HCl can be used; more preferably, about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used.
  • Bronsted bases are potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), triethylamine (“TEA”), pyridine, sodium acetate (“NaOAc”), sodium bicarbonate (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“NazS”), imidazole, potassium /c/7-butoxide (“KO/Bu”), and .V,A'-diisopropylethylamine (“DIPEA”). Sodium sulfide and triethylamine are preferred.
  • the reaction in Scheme Four can be conducted in the presence of a polar aprotic or a polar protic solvent or a nonpolar aprotic solvent.
  • polar aprotic solvents are tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), butyronitrile, cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), ethyl acetate (“EtOAc”), isopropyl acetate (“z-PrOAc”), A'-di methyl form am ide (“DMF”), A, V-dimethylacetamide (“DMAC”), isobutyl acetate (“/-BuOAc”), methyl ethyl ketone (“MEK”), dichloromethane (“DCM”), chlorobenzene (“PhQ”), and acetone.
  • polar protic solvents are //-butanol (“n-BuOH”), ec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z'-PrOH”), //-propanol (“//-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”).
  • An example of a nonpolar aprotic solvent is toluene (“PI1CH3”).
  • PI1CH3 nonpolar aprotic solvent
  • mixtures of such solvents may be used. Water and toluene are preferred.
  • the reaction in Scheme Four may be conducted at ambient temperatures, pressures and pH. However, higher or lower temperatures, pressures and pH may be used. Currently, temperatures from about -10 °C to about 100 °C may be used; preferably temperatures from about 35 °C to 70 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used. Currently, a pH from 6 to 13 may be used; preferably a pH from about 8 to 10 may be used.
  • reaction in Scheme Four-A converts S4A-a to the pyridylthi azole S5a in the presence of a Lewis or Bronsted acid. In some cases the reaction may result in an intermediate S5A-a requiring further manipulation to arrive at S5a.
  • Lewis acids or Bronsted acids are phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCI5”), trifluoromethanesulfonic anhydride (“TfzO”), trifluoroacetic anhydride (“TFAA”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethylsilyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), >-toluenesulfonic acid (“ -TSA”), sulfur
  • Phosphorus oxychloride and phosphorus trichloride are preferred.
  • Other Lewis acids or Bronsted acids may be used resulting in an intermediate requiring further manipulation to arrive at S5a.
  • about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mol of S4A-a can be used; more preferably, about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4A-a can be used.
  • the reaction can be conducted in the presence of a presence of a polar aprotic or a nonpolar aprotic solvent.
  • polar aprotic solvents are tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), chlorobenzene (“PhQ”), and ethyl acetate (“EtOAc”).
  • a nonpolar aprotic solvent is toluene (“PhCFL”).
  • mixtures of such solvents may be used.
  • Acetonitrile is preferred.
  • the reaction in Scheme Four-A may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 45 °C to 75 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.
  • kPa kilopascal
  • reaction in Scheme Four-A to produce amine S5A-a may be conducted under flow conditions.
  • the reaction in Scheme Five is conducted in the presence of 3-pyridinecarboxaldehyde, also known as ni cotinaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid which promotes the formation of S5a from S4a or S4a-HCl.
  • 3-pyridinecarboxaldehyde also known as ni cotinaldehyde
  • a Bronsted base sulfur
  • a Lewis acid or Bronsted acid which promotes the formation of S5a from S4a or S4a-HCl.
  • about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl can be used; more preferably, about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used.
  • 3-pyridinecarboxaldehyde examples include the neat form or as an aqueous acidic solution both of which can be used.
  • about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used.
  • about 0.05 mole to about 5 moles of Bronsted base per mol of S4a or S4a-HCl can be used; more preferably, about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used.
  • 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mol of S4a or S4a-HCl can be used; more preferably, about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCI can be used.
  • Bronsted bases are potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), triethylamine (“TEA”), pyridine, sodium acetate (“NaOAc”), sodium bicarbonate (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“Na2S”), imidazole, potassium tert-butoxide (“KO/Bu”), and A,A-diisopropylethylamine (“DIPEA”). Sodium sulfide and triethylamine are preferred.
  • Lewis acids or Bronsted acids are phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCh”), trifluoromethanesulfonic anhydride (“TfzO”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”),/?-toluenesulfonic acid (“ -TSA”), sulfuric acid (“H2SO4”), and solid supported acidic acid
  • the reaction in Scheme Five can be conducted in the presence of a polar aprotic or a nonpolar aprotic solvent.
  • polar aprotic solvents are tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), chlorobenzene (“PhCl”), and ethyl acetate (“EtOAc”).
  • An example of a nonpolar aprotic solvent is toluene (“PhCEL”). Optionally, mixtures of such solvents may be used. Acetonitrile is preferred.
  • the reaction in Scheme Five may be conducted at ambient temperatures and pressures.
  • temperatures and pressures may be used.
  • temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 35 °C to 70 °C may be used.
  • pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.
  • reaction in Scheme Five to produce amine S5A-a (Scheme Four-A) and S5a may be conducted under flow conditions.
  • the reaction in Scheme Six is conducted in the presence of a base.
  • the treatment of S5a with a base initially produces the free-base form of S5a (S5A-a shown in Example 12) which reacts with S2a to form S6a or S6a-HCl.
  • bases are organic bases and inorganic bases.
  • organic bases are pyridine, lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), /V,,V-di isopropyl ethyl amine (“DIPEA”), and triethylamine (“TEA”).
  • inorganic bases examples include potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCOs”), and sodium hydroxide (“NaOH”).
  • K2CO3 potassium carbonate
  • KHCO3 potassium bicarbonate
  • KOH potassium hydroxide
  • Na2CO3 sodium carbonate
  • NaHCOs sodium bicarbonate
  • NaOH sodium hydroxide
  • the coupling reaction with S2a can also be catalyzed by a reagent such as N, A-dimethylpyridin-4-amine (“DMAP”) or A-m ethyl imidazole (“NMI”).
  • DMAP A-dimethylpyridin-4-amine
  • NI A-m ethyl imidazole
  • the reaction in Scheme Six is conducted in the presence of a polar aprotic solvent or nonpolar aprotic solvents.
  • polar aprotic solvents are ethyl acetate (“EtOAc”), isobutyl acetate (“/-BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane (“DCM”), chloroform (“CHCh”), acetonitrile (“ACN”), and benzonitrile (“PhCN”).
  • EtOAc ethyl acetate
  • /-BuOAc tetrahydrofuran
  • 2-MeTHF 2-methyltetrahydrofuran
  • DCM dichloromethane
  • CHCh chloroform
  • ACN acetonitrile
  • PhCN benzonitrile
  • a nonpolar aprotic solvent is toluene (“PhCHs”).
  • mixtures of such solvents may
  • the reaction in Scheme Six may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 0 °C to 60 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.
  • kPa kilopascal
  • the product of Scheme Six may be isolated as the free-base form S6a or as an agriculturally acceptable acid addition salt form of S6a.
  • agriculturally acceptable acid addition salts include the hydrochloride (“HC1 salt”, S6a-HCl) and the hydrobromide (“HBr salt”), of which the hydrochloride salt is preferred.
  • S6a may be isolated from polar protic (e.g., water and alcohols such as methanol), polar aprotic, or nonpolar solvents or mixtures thereof.
  • a base may be used.
  • N- Ethyl-3-(methylsulfonyl)-7V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) or /V-ethyl-3- (methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl )propanamide hydrochloride (S6a-HCl) is chlorinated to form A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3- (methylsulfonyl)propanamide (S7a).
  • chlorinating agents examples include chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), A-chlorophthalimide (“NCP”), /V-chlorosaccharin (“NCSH”), tert- butylhypochlorite, chloramine-T, A-chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), and sodium hypochlorite. Chlorine or sodium hypochlorite are preferred.
  • the reaction in Scheme Seven is conducted in the presence of a polar solvent.
  • polar aprotic solvents are 1,4-di oxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2- MeTHF”), acetonitrile (“ACN”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”) and isobutyl acetate (“/-BuOAc”).
  • polar protic solvents are //-butanol (“//-BuOH”), isopropanol (“z-PrOH”), //-propanol (“n-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid (“AcOH”), formic acid (“HCOOH”), and aqueous hydrochloric acid (“HC1”).
  • Aqueous HC1 is preferred.
  • mixtures of such solvents may be used.
  • the reaction in Scheme Seven may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used, preferably temperatures from about 0 °C to 50 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.
  • kPa kilopascal
  • a catalyst may be used in the process to promote the reaction from Sla to Sib when the oxidizing agent used is hydrogen peroxide (H2O2).
  • H2O2 hydrogen peroxide
  • An example of a catalyst is sodium tungstate.
  • a base may be used to promote the reaction of Sib to the activated form S2a.
  • bases include lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), A-methylmorpholine, tri ethylamine (“TEA”), and MA'-diisopropylethylamine (“DIPEA”).
  • lutidine e.g., 2,6-lutidine and 3,5-lutidine
  • picoline e.g., 2-picoline and 3-picoline
  • A-methylmorpholine e.g., tri ethylamine (“TEA”), and MA'-diisopropylethylamine (“DIPEA”).
  • TEA tri ethylamine
  • DIPEA MA'-diisopropylethylamine
  • amine S4a may be isolated as a solution by extraction from the reaction solvent with a polar or a nonpolar solvent.
  • polar solvents are polar aprotic solvents and polar protic solvents.
  • polar aprotic solvents examples include tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”), 2-butanone, 4-methylpentan-2-one (“MIBK”), isopropyl acetate (“z-PrOAc”), //-butyl acetate, (“//-BuOAc”), dimethylcarbonate (“DMC”), methyl tert- butyl ether, (“MTBE”), anisole, butyronitrile, and acetonitrile (“ACN”).
  • THF tetrahydrofuran
  • 2-MeTHF dichloromethane
  • EtOAc ethyl acetate
  • MIBK 4-methylpentan-2-one
  • z-PrOAc isopropyl acetate
  • //-BuOAc dimethylcarbonate
  • DMC methyl tert
  • polar protic solvents examples include ec-butanol (“s-BuOH”) and 4-methyl-2-pentanol (“MIBC”).
  • MIBC 4-methyl-2-pentanol
  • nonpolar solvent examples of polar protic solvents
  • toluene examples of nonpolar solvents
  • mixtures of such solvents may be used.
  • the 3-pyridinecarboxaldehyde (nicotinaldehyde) from the aqueous solution can be extracted using a polar aprotic or a nonpolar aprotic solvent and used in the reaction.
  • polar aprotic solvents are tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”), n- butyl acetate (“nBuOAc”), 2-butanone, and dimethylcarbonate (“DMC”).
  • nonpolar aprotic solvents are toluene and xylene. Optionally, mixtures of such solvents may be used. Toluene and ethyl acetate are preferred.
  • sulfuric acid (“H2SO4”) is the preferred Lewis or Bronsted acid.
  • temperatures from about 10 °C to 44 °C may be used.
  • the free amine S5A-a may be isolated.
  • the free-base S5A-a may be converted to the HC1 salt form, S5a, by treatment with anhydrous HC1 or aqueous HC1.
  • S5a may be utilized in the reaction without first producing the free-base form of S5a, S5A-a.
  • A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3- yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) is chlorinated to form A’-(4-chl oro-2- (pyndin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S7a) in the presence of a chlorinating agent, wherein the chlorinating agent includes an oxidizing agent.
  • An example of an oxidizing agent is potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO5 KHSO4 K2SO4 [CAS 70693-62-8] available from E.I. du Pont de Nemours and Company or its affiliates as OXONE®, a registered trademark of E.I. du Pont de Nemours and Company or its affiliates).
  • the reaction proceeds in the presence of a chloride source (e.g., the hydrogen chloride salt of S6a-HCl), or, for example, by the addition of chloride salt (e.g., sodium chloride) and/or or hydrochloric acid.
  • a chloride source e.g., the hydrogen chloride salt of S6a-HCl
  • chloride salt e.g., sodium chloride
  • ethylamine 70 wt% in water; 152 mL, 1912 mmol
  • Methyl glycinate hydrochloride S3 (20 g, 159 mmol) in water (40 mL) was added to the ethylamine by syringe pump over 2 hours. The solution was stirred at -5 °C. After 45 minutes, a 50 wt% aqueous solution of sodium hydroxide (12.7 g, 159 mmol) was added, and the reaction mixture was warmed to 25 °C.
  • the solution was concentrated at a reduced pressure of 0.9 kPa and a jacket temperature of 50 °C to provide an oil with white solid.
  • ACN 125 mL was added, and the resulting slurry was concentrated to 50% of the volume, at a reduced pressure of 6.7 kPa and a jacket temperature of 50 °C.
  • the slurry was fdtered and washed with ACN (50 mL).
  • the reaction was then equipped with a vacuum distillation apparatus and the bath was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized.
  • the bath temperature was decreased to 65 °C and the distillation was continued at a reduced pressure of 10 kPa until ethylamine was undetected in the bottoms.
  • S4a was isolated as a 25 wt% aqueous solution (149.72 g, 90% yield).
  • the reaction was then equipped with a vacuum distillation apparatus and the bath was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized.
  • the bath temperature was decreased to 65 °C and the distillation was continued at a reduced pressure of 10 kPa until ethylamine was undetected in the bottoms.
  • the contents were filtered and transferred to a 1-L jacketed reactor under nitrogen equipped with a mechanical stirrer, thermocouple, and condenser already containing acetonitrile (388.76 g, 494.61 m ) over 1 hour.
  • the temperature was increased to 91 °C to azeotropically distill out water and acetonitrile.
  • the temperature was decreased to 25 °C and the reactor contents were filtered to remove the salts and washed with acetonitrile (86.3 g, 109.80 mb) to provide S4a as a 12 wt% solution in acetonitrile (245.06 g, 94% yield).
  • the reaction was then cooled to 50 °C. Then, HC1 (16 wt% 94.7 g, 415.6 mmol) was added over 10 minutes and the reaction mixture was held for 15 minutes to allow the sweep to remove any potential H2S gas that is formed. Toluene (287 g, 331 .03 mL) was added over 5 minutes, and the solution was agitated for 30 minutes and then allowed to settle for 30 minutes. The organic and aqueous layers were collected separately, and the aqueous layer was returned to the reactor. The aqueous layer was heated to 55 °C and 345 g of 1 M NaOH was added portion-wise until pH ⁇ 6. The resulting slurry was cooled to 20 °C over 5 hours.
  • a 100-mL jacketed reactor under nitrogen equipped with a mechanical stirrer, thermocouple, and pH meter was charged with 15 wt% aqueous nicotinaldehyde (26.4 g, 36.97 mmol). 25 wt% Aqueous NaOH (17.55 mL) was added until pH 10. The solution was transferred to a 250-mL jacketed reactor equipped with a mechanical stirrer, reflux condenser, scrubber containing bleach and sodium hydroxide, and thermocouple flushed with nitrogen and already containing sulfur (1.51 g, 47.1 mmol).
  • Acetonitrile (96.17, 122.34 mL) and 30.0 wt% aqueous solution of S4a (15.6, 45.82 mmol) were then added. The suspension was stirred, and the mixture was heated to an internal temperature of 67 °C. The reaction was held under these conditions and monitored by HPLC analysis until complete (18 hours). The reaction was then cooled to 50 °C. Then, HC1 (16 wt% 17.11 g, 75.30 mmol) was added over 5 minutes and the reaction was held for 15 minutes to allow the sweep to remove any potential H2S gas that is formed.
  • the mixture was cooled to 50 °C and vacuum was applied to concentrate to 30 wt% product.
  • the mixture was cooled to 0 °C and held for 12 hours, then filtered onto a sintered frit under a light vacuum and a pad of nitrogen.
  • the mixture was stirred at 70 °C and gradually became a dark red orange solution.
  • the reaction was monitored by high-performance liquid chromatography (HPLC) for disappearance of nicotinaldehyde (which took ⁇ 5 hours).
  • HPLC high-performance liquid chromatography
  • the reaction mixture was cooled to 50 °C.
  • Phosphorus oxychloride POCI3, 99%; 6.70 mL, 77.8 mmol
  • the dark brown thin slurry/oil was stirred at 50 °C for 7 hours over which time a yellow slurry formed (monitored by HPLC).
  • the yellow-orange slurry was cooled to 15 °C and toluene (20 mL) was added.
  • A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (29.73 g, 55.5 wt%, 1 equiv, 48.61 mmol) was added to a 250 mL jacketed reactor equipped with a pH probe, overhead stirrer, nitrogen inlet, caustic scrubber, temperature probe and dosing unit inlet, followed by ethyl acetate (23.56 g, 267.4 mmol) and the mixture was stirred to provide a white slurry.
  • Aqueous sodium acetate (19.94 g, 72.92 mmol) was added in a single portion, followed by acetic acid (4.38 g, 72.92 mmol).
  • 10 wt% Aqueous sodium hypochlorite (45.23 g, 60.76 mmol) was added dropwise over 1 hour. 2 Hours after addition was complete the mixture was quenched with 32 wt% aqueous sodium thiosulfate (7.205 g, 14.58 mmol).
  • 25 wt% Aqueous sodium hydroxide (3.111 g, 19.44 mmol) was added dropwise until pH > 8. Agitation was stopped and the organic layer was transferred to a 1 L round bottom flask.
  • Water content in the organic layer was brought to ⁇ 1 wt% via azeotropic distillation using dry EtOAc at 20 kPa vacuum at 50 °C bath temperature.
  • the mixture post distillation was approximately 30 wt% by mass.
  • the mixture was heated to 70 °C and held for 30 minutes then cooled to 35 °C at which point spontaneous nucleation occurred.
  • the mixture was aged for 4 hours after which heptane (26.79 g, 267.4 mmol) was added dropwise. The mixture was finally cooled to 0 °C and held at that temperature for 6 hours.
  • A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride S6a-HCl (15.0 g, 85 wt%, 33.9 mmol) was added to a 250 mL round bottom flask with a stir bar, followed by water (38.5 g, 38.5 mL, 2.14 mol) (pH 4). The solution was cooled to 0 °C, and 10 wt% sodium hypochlorite (53.0 g, 71.2 mmol) was added dropwise over 30-45 minutes. The reaction was checked at 45 minutes and at 75 minutes by UPLC, showing that there was about 35% by LC area of starting material remaining.
  • the mixture was re-constituted in isopropyl acetate (34.6 g, 39.8 mL, 339 mmol), heated to 70 °C to solubilize, and then allowed to cool to room temperature overnight to induce crystallization.
  • the resulting slurry was filtered and washed with cyclohexane (40 mL).
  • a jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (70 wt%, 512 g, 7.95 mol) and was cooled to an internal temperature of -4 °C.
  • a solution of methyl glycinate hydrochloride S3 (200 g, 1 .58 mol) in water (307 g) was gradually added to the ethylamine reactor. The temperature was held at -3 °C, and the reaction mixture was stirred for 1-3 hours. After the reaction was complete, the temperature was increased to 0 °C.
  • a 50 wt% aqueous solution of sodium hydroxide (130 g, 1.63 mol) was added over 10 minutes, and the reaction mixture was stirred for 30 minutes.
  • the reactor was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized.
  • the reactor temperature was decreased to 40 °C, the pressure was reduced to 10 kPa, and the distillation was continued by increasing the temperature to 65 °C until ethylamine was undetected in the bottoms.
  • the reactor contents were extracted twice with .s- BuOH (231 g, 3.12 mol).
  • a 5-L jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (67 wt%, 1040 g, 15.5 mol) and extra water (600 g, 33.3 mol) and was cooled to an internal temperature of -4 °C.
  • Solid methyl glycinate hydrochloride S3 (50.49 g, 398.13 mmol) was gradually added to the ethylamine reactor over 4 hours. The temperature was increased to 0 °C, and the reaction mixture was stirred for 2 hours.
  • a 48 wt% aqueous solution of sodium hydroxide (258 g, 3.1 mol) was added over 20 minutes.
  • the reactor was warmed to 80 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized.
  • the reactor temperature was decreased to 60 °C, the pressure was reduced to 10 kPa, and the distillation was continued by increasing the temperature to 75 °C until ethylamine was undetected in the bottoms.
  • MIBC (1600 g, 15.5 mol) was added, and the contents were distilled further at 75 °C and 8.5-10 kPa to remove water.
  • the slurry was filtered, and the solids were washed with MIBC (200 g, 1.94 mol).
  • the filtrates were combined and aqueous HC1 (35%, 355 g, 3.41 mol) was added.
  • ethyl acetate 102 g was added via an addition funnel, under agitation.
  • an aqueous solution of nicotinaldehyde (16.76% nicotinaldehyde by weight, 102 g) was added.
  • Sodium sulfate Na2SC>4, 20 g was added to the reactor, followed by addition of commercially obtained 2.5 M NaOH solution (20 m ).
  • the reactor was heated until the temperature of the reaction mixture reached 41 °C.
  • the contents were stirred at 270 rpm for 10 minutes. The stirring was stopped, and the two layers were allowed to separate and settle.
  • the aqueous layer and organic layer were collected separately and weighed.
  • Toluene 60 g was charged to the reactor, and the two phases were agitated at 40 °C. Stirring was stopped and the layers were allowed to settle. The aqueous layer and organic layer were collected separately, and the two organic layers were combined. The organic layer was analyzed using GC, and the nicotinaldehyde content in the solution was found to be 13.66 wt%.
  • a 70% saturated Na2SCU solution (53.8 g, 50.0 mL) was added.
  • the reaction mixture was thoroughly mixed for 10 minutes at 450 rpm and allowed to settle for 5 minutes.
  • the aqueous layer was removed.
  • the organic layer was diluted with hot ethyl acetate (31.5 g, 30.0 mL).
  • the resulting solution was heated to 65 °C and stirred at 300 rpm for 1 hour.
  • the solution was slowly cooled to 40 °C over 14 hours.
  • the seed slurry of S4A-a (0.104 g) in ethyl acetate (2.82 g) was added, and the reaction mixture was non-linearly cooled to 0 °C over 6 hours.
  • the resulting slurry was fdtered.
  • the reaction was held under these conditions and monitored by HPLC analysis until complete (19 hours).
  • the reaction mixture was stirred at 85 °C, and water (55 g, 55 mL) was added.
  • the solution was then cooled gradually to 10 °C over 4 hours.
  • the slurry was filtered, and the cake was washed with water (55 mL) and toluene (2 x 70 mL).
  • cone sulfuric acid 69.3 g, 37.7 mL, 95 wt%, 10 equiv, 672 mmol.
  • the reactor was cooled to 15 °C, and V-ethyl-2-(pyridine-3- carbothioamido)acetamide S4A-a (15.0 g, 1 equiv, 67.2 mmol) was added portion-wise over 30 minutes with overhead stirring set at 650 rpm and maintaining the internal temperature below 26 °C during the complete addition.
  • the jacket temperature was set at 40 °C, and the mixture was stirred vigorously (650 rpm) for 4 hours.
  • the reaction mixture was cooled to ambient temperature and stirred overnight.
  • reaction mixture was cooled to 10 °C, and water (80 mL) was added dropwise over 30 minutes with temperature never exceeding 25 °C.
  • the resulting aqueous solution was then treated dropwise with 10 M KOH in water over 30 minutes until the reaction mixture became thick and heterogeneous and the pH was measured as 7-8.
  • the slurry was drained into a filter funnel and washed with water (2 x 50 mL).
  • the filter cake was dried in a vacuum oven at 50 °C until dry to provide 2V-ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine S5A-a
  • the acetonitrile and PCh were removed by solvent exchange distillation with toluene (1172.7 g, 12.728 mol) at 50 °C under vacuum of ⁇ 20 kPa. The vacuum was removed, and the mixture was cooled to 25 °C. Water (229.10 g, 12.728 mol) was added, and the pH was adjusted to 8.0-8.5 with 50% potassium carbonate solution (508.7 g, 1.840 mol) at 25 °C. The mixture was heated to 50-55 °C, and the mixture was stirred for 30 minutes and allowed to settle for 30 minutes. The aqueous layer was separated, and the organic layer was set aside.
  • Dry HC1 gas (58.1 g, 1.591 mol) was passed through the mixture at 25-30 °C over 1 hour. The mixture was maintained at 25-30 °C for 1 hour. The solid was filtered, and the mother liquor was separated. The wet cake was washed with acetonitrile (260.8 g, 6.353 mol) and allowed to dry for 15 minutes under nitrogen atmosphere. Acetonitrile (260.8 g, 6.353 mol) was added to the wet cake, and the mixture was slurried and allowed to dry for 15 minutes under nitrogen atmosphere. The wet cake was dried at 40 °C under vacuum of ⁇ 6.7 kPa.
  • S5A-a was prepared in solution from S5a according to the procedure in Example 12. Dichloromethane was removed by distillation, and the solids were dried under vacuum at 40 °C for 16 hours to afford S5A-a as a yellow solid (95%).
  • S5A-a (4.01 g, 1 equiv, 19.5 mmol) was charged into a 100 mL glass reactor at ambient conditions. DCM (80.9 g, 953 mmol) and 3,5- dimethylpyridine (2.99 g, 1.4 equiv, 27.9 mmol) were added, and the solution was agitated. The solution of S5A-a was transferred into the solution of 3-(methylsulfonyl)propanoic pivalic anhydride at 33 °C.
  • the reaction mixture was stirred for 19 hours at 29-34 °C.
  • the mixture was concentrated by vacuum distillation at 50-55 °C to 24 mL.
  • ACN (31.0 g, 755 mmol) was added, and the mixture was concentrated by vacuum distillation at 55-60 °C to 24 mL.
  • Water (24.1 g, 1340 mol) and ACN (6.3 g, 153 mmol) were added to the mixture at 55 °C, and the mixture was concentrated by vacuum distillation at 55-66 °C to 24 mL.
  • the slurry was cooled to 10 °C over 4 hours, maintained at 10 °C for 1 hour, and fdtered.
  • S5A-a was prepared in solution from S5a according to the procedure in Example 12. Dichloromethane was removed by distillation and the solids were dried under vacuum at 40 °C for 16 hours to afford S5A-a as a yellow solid (95%).
  • S5A-a (4.00 g, 1 equiv, 19.5 mmol) was charged into a 100 mL glass reactor at ambient conditions. DCM (42.2 g, 497 mmol) and 3,5- dimethylpyridine (3.22 g, 1.5 equiv, 30.0 mmol) were added, and the solution was agitated. The solution of S5A-a was transferred into the solution of 3-(methylsulfonyl)propanoic pivalic anhydride at 35 °C.
  • the reaction mixture was stirred for 20 hours at 29-34 °C.
  • Methanol (31.6 g, 989 mmol) was added to the mixture, and the mixture was concentrated by vacuum distillation to 20 mL.
  • Methanol (31.6 g, 989 mmol) was added, and the mixture was concentrated by vacuum distillation to 20 mL.
  • Methanol (15.8 g, 494 mmol) was added to the mixture at 50 °C.
  • the slurry was cooled to 10 °C over 3 hours, maintained at 10 °C for 1 hour, and filtered.
  • the mixture was concentrated by vacuum distillation to half the volume, methanol (7.92 g, 10.0 mL, 49.4 equiv, 247 mmol) was added, and the mixture was re-concentrated by vacuum distillation to 20 mL reaction volume. Methanol (7.92 g, 10.0 mL, 49.4 equiv, 247 mmol) was added to the mixture at 25 °C. The slurry was cooled to 5 °C, held for 1 hour, and then filtered.
  • Chlorine gas (9.1 g, 128 mmol) was added slowly through a glass tube submerged under the liquid surface over 50 minutes. Upon reaction completion, 36 wt% aqueous sodium bisulfite (12.4 g, 48 mmol) was added, and the mixture was stirred for 60 minutes. Ethyl acetate (131.4 g, 1.49 mol) was added to the reactor. Aqueous sodium hydroxide (50 wt%, 25.5 g, 319 mmol) was added to bring the pH up to 7. The reactor was warmed to 35 °C. The phases were allowed to settle and separate. The organic layer was washed with water (69.8 g, 3.87 mol) and was cooled to 30 °C.
  • A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (12.50 g, 85 wt%, 1 equiv, 28.27 mmol) was added to a 250 mL jacketed reactor, followed by water (37.69 g, 37.69 mL, 74 equiv, 2.092 mol). The mixture was stirred at 23 °C.
  • Oxone® (20.85 g, 1.2 equiv, 33.92 mmol) in water (63.67 g, 63.67 mL, 125 Eq, 3.533 mol) (pH of —2.5) was prepared separately in a round bottom flask with agitation. The solution of Oxone® was added drop wise to the jacketed reactor over 1 hour, and the mixture was stirred. After complete conversion was observed, sodium bisulfite (8.823 g, 40 wt%, 1 .2 equiv, 33.92 mmol) was added dropwise over 15 minutes.
  • Potassium carbonate (23.44 g, 20 wt%, 1 .2 equiv, 33.92 mmol) was added dropwise to bring the pH to 10.
  • Isobutyl acetate (32.83 g, 41.8 mL, 10 equiv, 282.7 mmol) was added in a single portion, and the mixture was heated to 50 °C. The phases were separated, and the organic layer was set aside. Additional isobutyl acetate (32.83 g, 41.8 mL, 10 equiv, 282.7 mmol) was added in a single portion to the aqueous layer and the mixture was heated to 50 °C. The phases were separated, and the organic layer was set aside.
  • the combined organic layers were put under vacuum at 50 °C to concentrate the mixture via azeotrope down to ⁇ 1.0 wt% water. After reaching the desired water level, the mixture was heated to 65-70 °C to solubilize all of the material, and then allowed to cool to 0 °C over 12 hours. The mixture was maintained for 4 hours and then filtered.
  • oxidizing agent is oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peroxides, organic peracids (-OOH), potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO5 KHSO4 K2SO4 [CAS 70693-62-8]), or mixtures thereof.
  • the oxidizing agent, hydrogen peroxide (H2O2) further comprises the catalyst, sodium tungstate.
  • a process comprising reacting Sib in the presence of a carboxylic acid activator and an aprotic solvent to produce S2a
  • lOd A process according to detail 9d wherein from about 1.0 moles to about 5 moles of carboxylic acid activator per mole of Sib is used.
  • l id A process according to detail 9d wherein from about 1.0 moles to about 1.5 moles of carboxylic acid activator per mole of Sib is used.
  • a process according to detail 12d wherein the catalyst is A,A-dimethylformamide, /V-formylpyrrolidine, A-formylpiperidine, or mixtures thereof.
  • lutidine e.g., 2,6-lutidine and 3,5-lutidine
  • picoline e.g., 2-picoline and 3-picoline
  • A-methylmorpholine ethylamine
  • TEA tri ethylamine
  • DIPEA A-di isopropyl ethyl amine
  • 19d A process according to details 16d and 17d wherein from about 0.5 moles to about 1.2 moles of base per mole of Sib is used. 20d. A process according to details 9d, lOd, l id, 12d, 13d, 14d, 15d, 16d, 17d, 18d, and 19d wherein the aprotic solvent is a polar aprotic solvent, a nonpolar aprotic solvent, or a mixture thereof.
  • a process comprising aminating S3/3a to S4a or S4a-HCl with ethylamine in the presence of a secondary base and optionally a polar or a nonpolar solvent,
  • a process according to detail 26d wherein the amount of ethylamine used is from about 5 moles to about 12 moles of ethylamine per mole of S3/3a.
  • a process comprising reacting S4a or S4a-HCl with 3-pyridinecarboxaldehyde, in the presence of sulfur, a Bronsted base, and a solvent, to produce S4A-a
  • K2CO3 potassium carbonate
  • K3PO4 potassium phosphate
  • TAA triethylamine
  • pyridine sodium acetate
  • NaHCCh sodium bicarbonate
  • NaHCCh sodium hydrosulfide
  • NaSH sodium hydrosulfide
  • NazS sodium sulf
  • THF
  • a process according to any of the previous details 46d through 59d wherein the pressure at which this reaction is conducted is from ambient to 1000 kilopascal (kPa). 6 Id. A process according to any of the previous details 46d through 59d wherein the pressure at which this reaction is conducted is from ambient to about 200 kPa.
  • a process comprising converting S4A-a in the presence of a Lewis or Bronsted acid to S5a optionally, the converting is conducted in the presence of a solvent.
  • a process according to detail 64d wherein the Lewis or Bronsted acid is phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCI5”), trifluoromethanesulfonic anhydride (“TfzO”), tri fluoroacetic anhydride (“TFAA”), boron trifluoride diethyl etherate (“BF.3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), >- toluenesulf,
  • a process according to detail 65d wherein the Lewis or Bronsted acid is phosphorus oxychloride (“POCI3”) or phosphorus trichloride (“PCI3”).
  • POCI3 phosphorus oxychloride
  • PCI3 phosphorus trichloride
  • THF tetrahydrofuran
  • 2-MeTHF 2-methyltetrahydrofuran
  • ACN acetonitrile
  • PhCN benzonitrile
  • CPME cyclopentylmethyl ether
  • DMC dimethyl carbonate
  • EtOAc ethyl acetate
  • PI1CH3 chlorobenzene
  • PhQ chlorobenzene
  • a process comprising reacting S4a or S4a-HCl to produce S5a wherein the reacting is conducted in the presence of 3-pyridinecarboxaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid
  • K2CO3 potassium carbonate
  • K3PO4 potassium phosphate
  • TAA triethylamine
  • pyridine sodium acetate
  • NaHCCh sodium bicarbonate
  • NaHCCh sodium hydrosulfide
  • NaSH sodium hydrosulfide
  • Lewis acid or Bronsted acid is phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCls”), trifluoromethanesulfonic anhydride (“TfzO”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf ’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), p
  • THF tetrahydrofuran
  • 2-MeTHF 2-methyltetrahydrofuran
  • ACN acetonitrile
  • PhCN benzonitrile
  • CPME cyclopentylmethyl ether
  • DMC dimethyl carbonate
  • chlorobenzene PhCl
  • EtOAc ethyl acetate
  • toluene PhCFL
  • a process comprising coupling S5a with S2a to produce S6a or S6a-HCl wherein the coupling is conducted in the presence of a base, a solvent, and optionally a catalyst
  • DIPEA triethylamine
  • K2CO3 potassium carbonate
  • KHCO3 potassium bicarbonate
  • KOH potassium hydroxide
  • Na2CO3 sodium carbonate
  • NaHCO3 sodium bicarbonate
  • NaOH sodium hydroxide
  • 112d A process according to detail 11 Id wherein the solvent is ethyl acetate (“EtOAc”), isobutyl acetate (“z-BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane (“DCM”), chloroform (“CHCI3”), acetonitrile (“ACN”), benzonitrile (“PhCN”), toluene (“PhCH?”), or mixtures thereof.
  • 113d A process according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, l lOd,
  • a process according to detail 115d wherein the pressure is from ambient to about 200 kPa may be used.
  • chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), A-chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), tert- butylhypochlorite, chloramine-T, A -chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), sodium hypochlorite, or mixtures thereof.
  • the chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), A-chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), tert- butylhypochlorite, chloramine-T, A -chlorobenzotri azole (“NCBT”), trichloroisocyanuri
  • a process according to details 118d, 119d, and 120d wherein the chlorinating comprises contacting S6a-HCl and an oxidizing agent, preferably potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO.5 KHSCh K2SO4 [CAS 70693- 62-8]).
  • an oxidizing agent preferably potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO.5 KHSCh K2SO4 [CAS 70693- 62-8]).
  • the solvent is 1,4-dioxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acet
  • kPa kilopascal
  • composition comprising the molecule according to detail 135d and HC1.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une molécule, N-éthyl-3-(méthylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) ou son sel chlorhydrate (S6a-HCl), et des procédés pour préparer du S6a, du S6a-HCl, et du N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-éthyl-3-(méthylsulfonyl)propanamide (S7a), la molécule étant utile comme pesticide pour lutter contre des organismes nuisibles des phylums Arthropoda, Mollusca et Nematoda.
PCT/US2024/014736 2023-02-07 2024-02-07 Procédés associés à la formation de n-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-n-éthyl-3-(méthylsulfonyl)propanamide WO2024168001A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4621138A (en) * 1984-04-05 1986-11-04 Bayer Aktiengesellschaft Triphendioxazine dyestuffs
US4670583A (en) * 1984-09-12 1987-06-02 Taiho Pharmaceutical Company, Limited Amide compounds
US20100292253A1 (en) * 2009-05-05 2010-11-18 Dow Agrosciences Llc Pesticidal compositions
US20150111731A1 (en) * 2013-10-22 2015-04-23 Dow Agrosciences Llc Pesticidal compositions and related methods
WO2021158455A1 (fr) * 2020-02-04 2021-08-12 Dow Agrosciences Llc Compositions ayant une utilité pesticide et procédés associés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4621138A (en) * 1984-04-05 1986-11-04 Bayer Aktiengesellschaft Triphendioxazine dyestuffs
US4670583A (en) * 1984-09-12 1987-06-02 Taiho Pharmaceutical Company, Limited Amide compounds
US20100292253A1 (en) * 2009-05-05 2010-11-18 Dow Agrosciences Llc Pesticidal compositions
US20150111731A1 (en) * 2013-10-22 2015-04-23 Dow Agrosciences Llc Pesticidal compositions and related methods
WO2021158455A1 (fr) * 2020-02-04 2021-08-12 Dow Agrosciences Llc Compositions ayant une utilité pesticide et procédés associés

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