Methods relating to formation of n-(4-chloro-2-(pyridin-3-yl) thiazol-5-yl)-n-ethyl-3-(methylsulfonyl) propanamide

Abstract

The present disclosure relates to a molecular N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl) thiazol-5-yl) propanamide (S6a), or a hydrochloride salt thereof (S6a-HCl); and a process for the preparation of S6a, S6a-HCl; and N-(4-chloro-2-(pyridin-3-yl) thiazol-5-yl)-N-ethyl-3-(methylsulfonyl) propanamide (S7a) having a pesticidal effect on pests in Phyla Arthropoda, Phyla Mollusca and Phyla Nematoda.

Description

Background Art

[0001] The formation of 2-(pyridin-3-yl)thiazoles has been disclosed in applications WO 2010 / 129497; WO 2013 / 184475; WO 2013 / 184476; WO 2013 / 184480; and PCT / US2022 / 074322. DETAILED DESCRIPTION

[0002] Provided is the molecule N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide (also referred to herein as "S6a") or an agriculturally acceptable acid addition salt having the formula. Molecule S6a has demonstrated activity against green peach aphid (Myzus persicae), i.e., 71% control at 200 parts per million (ppm).

[0003]

[0004] An example of an agriculturally acceptable acid addition salt is the hydrochloride salt (also referred to herein as "S6a-HCl").

[0005] Additionally, methods for preparing and using molecules S6a or S6a-HCl are provided. Molecule S6a or S6a-HCl can be used in a method for preparing N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a).

[0006] The following is a method associated with the formation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (also referred to herein as "S7a") and is shown below.

[0007]

[0008] In embodiment 1 of scheme 1

[0009] Option 1

[0010]

[0011] The reaction in Scheme 1 is carried out in the presence of an oxidizing agent that oxidizes 3-(methylthio)propionic acid (also referred to herein as "S1a") to 3-(methylsulfonyl)propionic acid (also referred to herein as "S1b"). In other words, functionally, the oxidizing agent oxidizes the sulfide (-SCH3) to the sulfone (-S(=O)2CH3). Examples of oxidizing agents are oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peroxides, organic peracids (-OOH), and other inorganic oxidizing agents such as potassium peroxymonosulfate, potassium persulfate, potassium peroxymonosulfate sulfate (a triple salt having the formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8], which is available from EI du Pont de Nemours and Company or its affiliates as (available from E.I. DuPont de Nemours and Company or its affiliates). Typically, about 2 to about 4 moles of oxidant per mole of S1a can be used, preferably about 2.0 to about 3.0 moles of oxidant per mole of S1a. Mixtures of oxidants can also be used.

[0012] The reaction in scheme one is carried out in the presence of a polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), dichloromethane ("DCM"), acetone, acetonitrile ("ACN"), N,N-dimethylformamide ("DMF") and dimethyl sulfoxide ("DMSO"). Examples of polar protic solvents are acetic acid ("AcOH"), n-butanol ("n-BuOH"), isopropyl alcohol ("i-PrOH"), n-propyl alcohol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), formic acid ("HCOOH"), tert-butyl alcohol ("t-BuOH") and water ("H O"). Alternatively, a mixture of such polar solvents can be used.

[0013] The reaction in Scheme 1 can be carried out at ambient temperature (about 15°C to about 25°C) and an ambient pressure of about 95 kilopascals (kPa) to about 105 kPa (typically about 101 kPa). However, higher and lower temperatures and pressures can be used.

[0014] In the first embodiment of the second solution

[0015] Option 2

[0016]

[0017] in

[0018] A is Cl, O(C=O)R1, or OR1, wherein R1 is (C1-C4)alkyl.

[0019] The reaction in Scheme 2 is carried out in the presence of a carboxylic acid activating agent. The activated carboxylic acid S2a can include acyl chlorides, mixed anhydrides and esters. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with a dehydrating chlorination agent such as oxalyl chloride or thionyl chloride. Mixed anhydrides can be prepared from carboxylic acids and chloroformates (R1O(C=O)Cl) such as ethyl chloroformate, methyl chloroformate and isobutyl chloroformate or other acyl chlorides such as pivaloyl chloride. Esters can be produced by the reaction of S1b with alcohols such as methanol or ethanol under acidic conditions. Typically, about 1.0 moles to about 5 moles of activator / mole of S1b, more preferably about 1.0 moles to about 1.5 moles of activator / mole of S1b, can be used.

[0020] Alternatively, a catalyst may be used to promote the reaction of S1b to the activated form S2a. Examples of catalysts include N,N-dimethylformamide, N-formylpyrrolidine, and N-formylpiperidine. Typically, about 0.01 to 0.5 moles of catalyst per mole of S1b, more preferably about 0.05 to about 0.1 moles of catalyst per mole of S1b, may be used.

[0021] The reaction in Scheme 2 is carried out in the presence of an aprotic solvent. Examples of aprotic solvents are polar aprotic solvents and non-polar aprotic solvents. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl 3 "), acetonitrile ("ACN"), and benzonitrile ("PhCN"). An example of a non-polar aprotic solvent is toluene ("PhCH 3 "). Alternatively, a mixture of such solvents may be used.

[0022] The reaction in Scheme 2 can be carried out at ambient temperature and ambient pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about 0°C to about 100°C can be used, temperatures of about 50°C to about 80°C can be used, and preferably, temperatures of about 20°C to about 60°C can be used.

[0023] Compound S2a can be isolated and used or used directly in the subsequent reaction without isolation.

[0024] In one embodiment of scheme three

[0025] Option 3

[0026]

[0027] The reaction in Scheme 3 can provide an amine (S4a) or an amine hydrochloride (S4a-HCl).

[0028] Alternatively, the product of Scheme 3 can be prepared as a free amine (S4a) in one step from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride (also referred to herein as "S3 / 3a") by the reaction shown in Scheme 3 in the presence of ethylamine and a secondary base. Examples of secondary bases are organic bases and inorganic bases. Examples of organic bases are N,N-diisopropylethylamine ("DIPEA") and triethylamine ("TEA"). Examples of inorganic bases are potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3"), and sodium hydroxide ("NaOH"). Optionally, a secondary base can be added after the reaction is complete. Typically, about 1 to about 15 moles of ethylamine per mole of S3 / 3a can be used; more preferably, about 5 to about 12 moles of ethylamine per mole of S3 / 3a can be used. Typically, from about 0.8 moles to about 2 moles of secondary base per mole of S3 / 3a can be used; more preferably, from about 0.8 moles to about 1.2 moles of secondary base per mole of S3 / 3a can be used.

[0029] Alternatively, the reaction in scheme three is carried out in the presence of a polar or non-polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), anisole, and acetonitrile ("ACN"). Examples of polar protic solvents are n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropyl alcohol ("i-PrOH"), n-propyl alcohol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("H2O"). Examples of non-polar solvents are toluene ("PhCH3"). Alternatively, a mixture of such solvents can be used. Water is preferred.

[0030] The reaction in Scheme 3 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about -20°C to about 50°C can be used; preferably, temperatures of about -10°C to 10°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used.

[0031] Alternatively, amine S4a can be isolated as a solution in the reaction solvent. Preferably, S4a can be isolated as a 5 weight percent (wt%) to 40 weight percent (wt%) solution in acetonitrile, water or sec-butanol.

[0032] Alternatively, the reaction in Scheme 3 to produce amine S4a can be carried out under flow conditions. Flow conditions are known in the art. See, for example, Luis, Santiago V., and Eduardo García-Verdugo, eds., Chemical reactions and processes under flow conditions. Vol. 5, Royal Society of Chemistry, 2010.

[0033] Alternatively, after reaction with ethylamine, S4a can be converted into a hydrochloric acid (HCl) salt (S4a-HCl) by treatment with anhydrous HCl or aqueous HCl. Typically, about 1 to about 10 moles of HCl / mole of S4a can be used; more preferably, 1 to about 3 moles of HCl / mole of S4a can be used. The formation of the HCl salt form is carried out in the presence of a polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are 1,4-dioxane, ethyl acetate ("EtOAc"), methyl tert-butyl ether ("MTBE"), and cyclopentyl methyl ether ("CPME"). Examples of polar protic solvents are sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropyl alcohol ("i-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("H2O"). Alternatively, mixtures of such polar solvents with each other or with non-polar solvents such as toluene may be used.

[0034] In one embodiment of scheme 4

[0035] Option 4

[0036]

[0037] The reaction in Scheme 4 converts S4a or S4a-HCl into pyridylthioamide S4A-a using 3-pyridinecarboxaldehyde (nicotinaldehyde) in the presence of sulfur and a base in a solvent.

[0038] The reaction in Scheme 4 is carried out in the presence of 3-pyridinecarboxaldehyde (also known as nicotinaldehyde), a Bronsted base, and sulfur. Typically, about 0.5 to about 5 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used; more preferably, about 0.7 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 pure form or aqueous solutions, both of which can be used. Typically, about 1 to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used. Typically, about 0.05 to about 5 moles of Bronsted base per mole of S4a or S4a-HCl can be used; more preferably, about 0.1 to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used. Examples of Bronsted bases are potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"). Sodium sulfide and triethylamine are preferred.

[0039] The reaction in Scheme 4 can be carried out in the presence of a polar aprotic or polar protic solvent or a nonpolar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), butyronitrile, cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), ethyl acetate ("EtOAc"), isopropyl acetate ("i-PrOAc"), N,N-dimethylformamide ("DMF"), N,N-dimethylacetamide ("DMAC"), isobutyl acetate ("i-BuOAc"), methyl ethyl ketone ("MEK"), dichloromethane ("DCM"), chlorobenzene ("PhCl"), and acetone. Examples of polar protic solvents are n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropyl alcohol ("i-PrOH"), n-propyl alcohol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("H2O"). An example of a non-polar aprotic solvent is toluene ("PhCH3"). Alternatively, mixtures of such solvents may be used. Water and toluene are preferred.

[0040] The reaction in Scheme 4 can be carried out at ambient temperature, pressure, and pH. However, higher or lower temperatures, pressures, and pHs can be used. Currently, temperatures of about -10°C to about 100°C can be used; preferably, temperatures of about 35°C to 70°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used. Currently, a pH of 6 to 13 can be used; preferably, a pH of about 8 to 10 can be used.

[0041] In one embodiment of Scheme 4-A

[0042] Option 4-A

[0043]

[0044] The reaction in Scheme 4-A converts S4A-a to pyridylthiazole S5a in the presence of a Lewis acid or a Bronsted acid. In some cases, this reaction can produce an intermediate S5A-a that requires further manipulation to provide S5a.

[0045] Examples of Lewis or Bronsted acids are phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), trifluoroacetic anhydride ("TFAA"), boron trifluoride diethyl etherate ("BF3.OEt2"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), trifluoromethanesulfonic acid ("TfOH"), methanesulfonic acid ("MsOH"), Eaton's reagent ("PO5-MsOH"), hydrogen bromide ("HBr"), aqueous hydrobromic acid ("HBr in water"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("H2SO4"), and solid-supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. Other Lewis or Bronsted acids may be used to generate intermediates that require further manipulation to provide S5a. Typically, about 0.5 to about 50 moles of Lewis or Bronsted acid per mole of S4A-a may be used; more preferably, about 1 to about 5 moles of Lewis or Bronsted acid per mole of S4A-a may be used.

[0046] In one embodiment of Scheme 4-A, the reaction can be carried out in the presence of a polar aprotic or non-polar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), and ethyl acetate ("EtOAc"). An example of a non-polar aprotic solvent is toluene ("PhCH3"). Alternatively, a mixture of such solvents can be used. Acetonitrile is preferred.

[0047] The reaction in Scheme 4-A can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about -10°C to about 80°C can be used; preferably, temperatures of about 45°C to 75°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used.

[0048] Alternatively, the reaction in Scheme 24-A to produce amine S5A-a can be carried out under flow conditions.

[0049] In one embodiment of scheme 5

[0050] Plan 5

[0051]

[0052] The reaction in Scheme 5 is carried out in the presence of 3-pyridinecarboxaldehyde (also known as nicotinaldehyde), a Bronsted base, sulfur, and a Lewis acid or Bronsted acid that promotes the formation of S5a from S4a or S4a-HCl. Typically, about 0.5 to about 5 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used; more preferably, about 0.7 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 pure form or acidic aqueous solutions, both of which can be used. Typically, about 1 to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used. Typically, about 0.05 to about 5 moles of Bronsted base per mole of S4a or S4a-HCl can be used; more preferably, about 0.1 to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used. Typically, about 0.5 to about 50 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCl can be used; more preferably, about 1 to about 5 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCl can be used. Examples of Bronsted bases are potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"). Sodium sulfide and triethylamine are preferred. Examples of Lewis or Bronsted acids are phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), boron trifluoride diethyl etherate ("BF3.OEt2"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), trifluoromethanesulfonic acid ("TfOH"), methanesulfonic acid ("MsOH"), Eaton's reagent ("PO5-MsOH"), hydrogen bromide ("HBr"), aqueous hydrobromic acid ("HBr in water"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("H2SO4"), and solid-supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. In some cases, this reaction can produce intermediates that require further manipulation to provide S5a.

[0053] The reaction in Scheme 5 can be carried out in the presence of a polar aprotic or non-polar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), and ethyl acetate ("EtOAc"). An example of a non-polar aprotic solvent is toluene ("PhCH3"). Alternatively, a mixture of such solvents can be used. Acetonitrile is preferred.

[0054] The reaction in Scheme 5 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about -10°C to about 80°C can be used; preferably, temperatures of about 35°C to 70°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used.

[0055] Alternatively, the reaction in Scheme 5 to produce amines S5A-a (Scheme 4-A) and S5a can be performed under flow conditions.

[0056] In one embodiment of scheme six

[0057] Plan 6

[0058]

[0059] The reaction in scheme six is ​​carried out in the presence of a base. S5a is initially treated with a base to produce S5a (S5A-a shown in Example 12) in the form of a free base, which is reacted with S2a to form S6a or S6a-HCl. Examples of bases are organic bases and inorganic bases. Examples of organic bases are pyridine, lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N,N-diisopropylethylamine ("DIPEA") and triethylamine ("TEA"). Examples of inorganic bases are potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3") and sodium hydroxide ("NaOH"). Typically, about 1 to about 5 moles of base per mole of S5a can be used; more preferably, about 2.0 to about 3.5 moles of base per mole of S5a can be used. The coupling reaction with S2a can also be catalyzed by reagents such as N,N-dimethylpyridin-4-amine ("DMAP") or N-methylimidazole ("NMI").

[0060] The reaction in Scheme 6 is carried out in the presence of a polar aprotic solvent or a non-polar aprotic solvent. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl 3 "), acetonitrile ("ACN"), and benzonitrile ("PhCN"). An example of a non-polar aprotic solvent is toluene ("PhCH 3 "). Alternatively, a mixture of such solvents may be used.

[0061] The reaction in Scheme VI can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about -10°C to about 80°C can be used; preferably, temperatures of about 0°C to 60°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used.

[0062] The product of scheme six can be separated into the free base form S6a or the agriculturally acceptable acid addition salt form of S6a. The example of agriculturally acceptable acid addition salt includes hydrochloride ("HCl salt", S6a-HCl) and hydrobromide ("HBr salt"), wherein hydrochloride is preferred. S6a can be separated from polar protic solvents (e.g., water and alcohol such as methanol), polar aprotic solvents or non-polar solvents or mixtures thereof. Alternatively, a base can be used.

[0063] In one embodiment of scheme seven

[0064] Plan 7

[0065]

[0066] The reaction in Scheme 7 is carried out in the presence of a chlorinating agent. N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide (S6a) or N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide hydrochloride (S6a-HCl) is chlorinated to form N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a). Typically, about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl can be used; more preferably, about 1.0 moles to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl can be used. Examples of the chlorinating agent include chlorine gas, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), and sodium hypochlorite. Chlorine gas or sodium hypochlorite is preferred.

[0067] The reaction in Scheme 7 is carried out in the presence of a polar solvent. Examples of polar aprotic solvents are 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), and isobutyl acetate ("i-BuOAc"). Examples of polar protic solvents are n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H2O"), acetic acid ("AcOH"), formic acid ("HCOOH"), and aqueous hydrochloric acid ("HCl"). Aqueous HCl is preferred. Alternatively, mixtures of such solvents may be used.

[0068] The reaction in Scheme 7 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about -10°C to about 80°C can be used; preferably, temperatures of about 0°C to 50°C can be used. Currently, pressures of ambient pressure to 1000 kilopascals (kPa) can be used; preferably, pressures of ambient pressure to about 200 kPa can be used.

[0069] In another embodiment of Scheme 1, when the oxidant used is hydrogen peroxide (H2O2), a catalyst may be used in the method to promote the reaction from S1a to S1b. An example of the catalyst is sodium tungstate.

[0070] In another embodiment of Scheme 2, optionally, a base can be used to promote the reaction of S1b to the activated form S2a. Examples of bases include lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N-methylmorpholine, triethylamine ("TEA"), and N,N-diisopropylethylamine ("DIPEA"). Typically, about 0.1 to 1.5 moles of base / mole of S1b, more preferably about 0.5 to about 1.2 moles of base / mole of S1b, can be used.

[0071] The reaction in Scheme 2 can be carried out at ambient temperature and ambient pressure. However, higher or lower temperatures and pressures can be used. Currently, temperatures of about 0°C to about 100°C can be used, and preferably, temperatures of about 20°C to about 49°C can be used.

[0072] In another embodiment of scheme three, alternatively, amine S4a can be separated into solution by extracting from reaction solvent with polar or non-polar solvent.The example of polar solvent is polar aprotic solvent and polar protic solvent.The example of polar aprotic solvent is tetrahydrofuran (" THF "), 2-methyltetrahydrofuran (" 2-MeTHF "), dichloromethane (" DCM "), ethyl acetate (" EtOAc "), 2-butanone, 4-methyl pentan-2-one (" MIBK "), isopropyl acetate (" i-PrOAc "), n-butyl acetate (" n-BuOAc "), dimethyl carbonate (" DMC "), methyl tert-butyl ether (" MTBE "), anisole, butyronitrile and acetonitrile (" ACN ").The example of polar protic solvent is sec-butyl alcohol (" s-BuOH ") and 4-methyl-2-pentanol (" MIBC ").The example of non-polar solvent is toluene.Alternatively, the mixture of this type of solvent can be used.

[0073] In another embodiment of scheme four, 3-pyridinecarboxaldehyde (nicotinaldehyde) from aqueous solution can be extracted using the polar aprotic or non-polar aprotic solvent used in the reaction. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), n-butyl acetate ("nBuOAc"), 2-butanone, and dimethyl carbonate ("DMC"). Examples of non-polar aprotic solvents are toluene and xylene. Alternatively, a mixture of such solvents can be used. Toluene and ethyl acetate are preferred.

[0074] In another embodiment of Scheme 4-A, sulfuric acid ("H2SO4") is a preferred Lewis acid or Bronsted acid. In another embodiment of Scheme 4-A, preferably, a temperature of about 10°C to 44°C can be used. In another embodiment of Scheme 4-A, the free amine S5A-a can be isolated.

[0075] In another embodiment of Scheme 24-A, the free base S5A-a can be converted to the HCl salt form S5a by treatment with anhydrous HCl or aqueous HCl.

[0076] In another embodiment of Scheme 6, S5a can be used in the reaction without first generating the free base form of S5a, S5A-a.

[0077] In another embodiment of Scheme VII, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) is chlorinated in the presence of a chlorinating agent to form N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a), wherein the chlorinating agent comprises an oxidizing agent. An example of an oxidizing agent is potassium peroxymonosulfate sulfate (a triple salt having the formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8], which is available from E.I. DuPont or its affiliates as (available from E.I. DuPont de Nemours and Company or its affiliates). The reaction is carried out in the presence of a chloride source (e.g., the hydrogen chloride salt of S6a-HCl), or, for example, by addition of a chloride salt (e.g., sodium chloride) and / or hydrochloric acid.

[0078] Examples

[0079] Example 1: Synthesis of 3-(methylsulfonyl)propionic acid (S1b)

[0080]

[0081] To a 5 liter (L) jacketed reactor equipped with a mechanical stirrer and a nitrogen inlet was added 3-(methylthio)propionic acid (S1a; 152.2 grams (g), 131 milliliters (mL), 1.267 moles (mol)), acetonitrile (3 L) and water (70 mL). The jacket was cooled to 20° C. and to the homogeneous clear solution was added portionwise (1191 g, 3.89 mol) to control the internal temperature to below 30°C. After the addition is complete, the white slurry is stirred until the internal temperature returns to 20°C (approximately 1 hour). The jacket is heated to 40°C. Once the reaction is complete, as described by 1The jacket was cooled to 20°C, and sodium bisulfite was added to quench the peroxide, as monitored by H NMR spectroscopy. After 60 minutes and confirmation of quenching of the peroxide, the solution was concentrated to a solid. The resulting white solid was dissolved in acetonitrile (1 L) to give a slurry with residual salts. The mixture was filtered to remove the salts, and the filtrate was concentrated to provide a white solid, which was dried in a vacuum oven at 40°C to give 3-(methylsulfonyl)propanoic acid (167 g, 88%), which was used as is in the next step: mp 94.0°C-99.2°C; 1 H NMR (500MHz, DMSO-d6) δ12.54(s,1H),3.33(t,J=7.5Hz,2H),3.00(s,3H),2.68(t,J=7.5Hz,2H); 13 C NMR (126MHz, DMSO-d6) δ171.12, 48.74, 39.62, 26.50.

[0082] Example 2: Synthesis of 3-(methylsulfonyl)propionyl chloride (S2a-1)

[0083]

[0084] 3-(Methylsulfonyl)propionic acid (S1b; 50 g, 329 mmol) and toluene (299 mL) were charged into a 500 mL three-necked round-bottom flask equipped with a nitrogen inlet, a reflux condenser, an exhaust pipe leading to a 1 equivalent (N) sodium hydroxide (NaOH) alkali scrubber, and a stirring rod to give a heterogeneous solution. Thionyl chloride (493.5 mmol) was added thereto, and the solution was heated to an internal temperature of 70°C-75°C. The reaction mixture was stirred at this temperature while monitoring the reaction to completion. The reaction mixture was cooled to room temperature when significant solid formation was observed. Heptane (250 mL) was added to the slurry, and the mixture was stirred for 10 minutes. The white solid was separated by filtration under nitrogen (to avoid degradation) and washed with heptane to produce a white solid (52.14 g, 93%): 1 H NMR (500MHz, CDCl3) δ3.51–3.46(m,2H),3.43–3.38(m,2H),3.00(s,3H); 13 C NMR (126MHz, CDCl3) δ171.8, 49.5, 41.6, 39.3.

[0085] Example 3: Synthesis of 3-(methylsulfonyl)propionyl chloride (S2a-1)

[0086]

[0087] 3-(Methylsulfonyl)propanoic acid (S1b; 2.04 g, 13.5 mmol) was charged into a three-necked 100 mL round-bottom flask equipped with a condenser, an overhead stirrer with a paddle impeller, a thermocouple, and a nitrogen outlet with a NaOH scrubber. Acetonitrile (31.8 g) was added to the flask and heated to 40° C. Thionyl chloride (1.86 g, 15.6 mmol) was added dropwise to the flask over ten minutes. The clear solution was maintained at 40° C. for 1 hour and 40 minutes (until proton NMR spectroscopy indicated a conversion of >98%). The solution of the acid chloride was used directly for amide coupling (Example 12). 1 H NMR (500MHz, CDCl3) δ3.51–3.46(m,2H),3.43–3.38(m,2H),3.00(s,3H); 13 C NMR (126MHz, CDCl3) δ171.8, 49.5, 41.6, 39.3.

[0088] Example 4: Synthesis of 2-amino-N-ethylacetamide (S4a)

[0089]

[0090] Ethylamine (70wt% in water; 152mL, 1912mmol) is added to a 250-mL jacketed reactor, and the solution is cooled to -5°C. Glycine methyl ester hydrochloride S3 (20g, 159mmol) in water (40mL) is added to ethylamine by a syringe pump over 2 hours. The solution is stirred at -5°C. After 45 minutes, 50wt% aqueous sodium hydroxide solution (12.7g, 159mmol) is added, and the reaction mixture is warmed to 25°C. The solution is concentrated at a reduced pressure of 0.9kPa and a jacket temperature of 50°C to provide an oily substance with a white solid. ACN (125mL) is added, and the resulting slurries are concentrated to 50% of volume at a reduced pressure of 6.7kPa and a jacket temperature of 50°C. The slurries are filtered and washed with ACN (50mL). The filtrate was concentrated under reduced pressure of 0.9 kPa and a jacket temperature of 50° C. to provide 2-amino-N-ethylacetamide (15.83 g) as a clear colorless oil: 1 HNMR (500MHz, DMSO-d6) δ7.78 (s, 1H), 3.14–3.06 (m, 2H), 3.04 (s, 2H), 1.02 (t, J = 7.2Hz, 3H); 13 C NMR (126MHz, DMSO-d6) δ173.04, 45.27, 33.50, 15.34.

[0091] Example 5: Synthesis of 2-amino-N-ethylacetamide (S4a)

[0092]

[0093] A 250-mL jacketed reactor equipped with a mechanical stirrer and a thermocouple under nitrogen was charged with a solution of ethylamine in water (66wt%-72wt%, 128.26g, 1991.24mmol) and cooled to an internal temperature of -4°C. A 40wt% solution of glycine methyl ester hydrochloride S3 (50.0g, 398.25mmol) in water (75g) was gradually added to the reactor over a 2-hour period, maintaining the temperature below 3°C. Sodium hydroxide (50%, 15.93g, 398.25mmol) was added over 10 minutes. The reaction was then equipped with a vacuum distillation apparatus and the bath was heated to 95°C to distill out methanol and ethylamine until the volume of the bottoms stabilized. The bath temperature was reduced to 65°C and distillation was continued under a reduced pressure of 10kPa until no ethylamine was detected in the bottoms. S4a was separated into a 25wt% aqueous solution (149.72g, 90% yield).

[0094] Example 6: Synthesis of 2-amino-N-ethylacetamide (S4a)

[0095]

[0096] In the 250-mL jacketed reactor equipped with a mechanical stirrer and a thermocouple under nitrogen, a solution of ethylamine in water (66wt%-72wt%, 127.45g, 1978.60mmol) is loaded and cooled to an internal temperature of -4°C. In 2 hours, a solution of glycine methyl ester hydrochloride S3 (50.49g, 398.13mmol) in water (75g) is gradually added to the ethylamine reactor. The temperature is raised to 0°C and the reaction mixture is stirred for 1 hour. In 10 minutes, 43wt% aqueous sodium hydroxide solution (37.05g, 398.82mmol) is added. The reaction is then equipped with a vacuum distillation apparatus and the bath is warming up to 95°C to distill out methanol and ethylamine, until the volume of the bottoms is stable. The bath temperature is reduced to 65°C and distillation is continued under a reduced pressure of 10kPa until no ethylamine is detected in the bottoms. Content is filtered and transferred in 1 hour to the 1-L jacketed reactor being equipped with mechanical stirrer, thermocouple and condenser under nitrogen already containing acetonitrile (388.76g, 494.61mL).The temperature is raised to 91 DEG C with azeotropic distillation water and acetonitrile.The temperature is reduced to 25 DEG C, and reactor contents is filtered to remove salt and washed with acetonitrile (86.3g, 109.80mL), to provide S4a (245.06g, 94% productive rate) in 12wt% solution in acetonitrile.

[0097] Example 7: Synthesis of 2-amino-N-ethylacetamide (S4a)

[0098]

[0099] Ethylamine (70wt% in water) (159mL, 2000mmol) is loaded into the 250mL jacketed reactor under nitrogen and the solution is cooled to-5 DEG C. In 2 hours, glycine ethyl ester hydrochloride S3a (55.8g, 400mmol) in water (75mL) is added to ethylamine by syringe pump. The solution is stirred at-5 DEG C. After 45 minutes, 45wt% potassium hydroxide aqueous solution (49.9g, 400mmol) is added, and the reaction mixture is warming up to 25 DEG C, forms white slurries during this period. Excess ethylamine is removed by distillation at 95 DEG C under ambient atmosphere. Subsequently, the system is slowly placed in vacuum under 10kPa to remove residual water until about 30wt%. The mixture is cooled to 5 DEG C and filtered to provide 2-amino-N-ethylacetamide S4a (109.5g, 86% yield) in a 32wt% aqueous solution: 1 H NMR (500MHz, DMSO-d6) δ7.78 (s, 1H), 3.14–3.06 (m, 2H), 3.04 (s, 2H), 1.02 (t, J = 7.2Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 173.04, 45.27, 33.50, 15.34. Example 8: Synthesis of N-ethyl-2-(pyridine-3-thiocarboxamido)acetamide (S4A-a)

[0100]

[0101] Under nitrogen and equipped with a mechanical stirrer, reflux condenser, a scrubber containing bleach and sodium hydroxide, and a thermocouple, a 1-L jacketed reactor was charged with sulfur (8.30 g, 258.81 mmol), potassium carbonate (2.82 g, 20.4 mmol), acetonitrile (365.84 g, 465.45 mL), a 25.9 wt% S4a aqueous solution (101.39 g, 257.1 mmol), and 98 wt% nicotinaldehyde (22.85 g, 209.1 mmol). The suspension was stirred and the mixture was heated to an internal temperature of 67°C. The reaction was maintained under these conditions and monitored by HPLC analysis until completion (18 hours). The reaction was then cooled to 50°C. HCl (16 wt%, 94.7 g, 415.6 mmol) was then added over 10 minutes and the reaction mixture was kept for 15 minutes to allow purging to remove any potential H2S gas formed. Toluene (287 g, 331.03 mL) was added over 5 minutes, and the solution was stirred for 30 minutes and then allowed to settle for 30 minutes. The organic layer and the aqueous layer 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 in batches until the pH was about 6. The resulting slurry was cooled to 20 ° C over 5 hours. The mixture was filtered, and the wet cake was washed twice with water. The wet cake was collected and dried in a vacuum oven at 50 ° C at 4 kPa to provide the title compound S4A-a (24.5 g) as a yellow solid: mp = 145 ° C; 1 H NMR (400MHz, CDCl3) δ9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.3 5(ddd,J=8.0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74; ESIMSm / z224.2([M+H] + ).

[0102] Example 9: Synthesis of N-ethyl-2-(pyridine-3-thiocarboxamido)acetamide (S4A-a)

[0103]

[0104] In the 100-mL jacketed reactor equipped with a mechanical stirrer, a thermocouple and a pH meter under nitrogen, a 15wt% nicotinaldehyde aqueous solution (26.4g, 36.97mmol) is loaded. Add the 25wt% NaOH aqueous solution (17.55mL) until pH 10. The solution is transferred to a 250-mL jacketed reactor equipped with a mechanical stirrer, a reflux condenser, a scrubber containing bleach and sodium hydroxide and a thermocouple that has been flushed with nitrogen and already contains sulfur (1.51g, 47.1mmol). Then acetonitrile (96.17, 122.34mL) and a 30.0wt% S4a aqueous solution (15.6, 45.82mmol) are added. The suspension is stirred, and heating the mixture to an internal temperature of 67°C. The reaction is maintained under these conditions and monitored by HPLC analysis until completion (18 hours). The reaction is then cooled to 50°C. Then, HCl (16wt%, 17.11g, 75.30mmol) was added within 5 minutes and the reaction was kept for 15 minutes to allow purging to remove any potential H2S gas formed. Toluene (73.6g, 84.89mL) was added within 5 minutes and the solution was stirred for 10 minutes and then allowed to settle for 5 minutes. The aqueous layer was removed. The organic layer was concentrated under vacuum. The resulting solid was resuspended in acetonitrile (50mL) and filtered. The wet cake was washed with acetonitrile (2x 50mL) and dried in a vacuum oven at 50°C under a reduced pressure of 4kPa to provide the title compound S4A-a (2.39g, 29% yield) as a yellow solid: mp 145°C; 1 HNMR(400MHz, CDCl3) δ9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.3 5(ddd,J=8.0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74. ESIMSm / z 224.2([M+H] + ).

[0105] Example 10: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a)

[0106]

[0107] N-ethyl-2-(pyridine-3-thiocarboxamido) ethanamide S4A-a (33.3g, 148mmol) is packed into the 1-L jacketed reactor that is equipped with mechanical stirrer, the reflux condenser with vacuum distilling apparatus, peristaltic pump and thermocouple under nitrogen.Add acetonitrile (132g, 168mL) and stir the mixture at 70 ℃.In 1 hour, drip POCl3 (47.6g, 310mmol), keep internal temperature lower than 80 ℃.Reaction is remained under these conditions and is analyzed and monitored until completion by HPLC.After 1 hour, reaction mixture significantly darkens during the reaction process.When observing that S4A-a consumes completely, mixture is cooled to 50 ℃ and applies vacuum to be condensed into 30wt% product.Mixture is cooled to 0 ℃ and kept 12 hours, then is filtered on sintered glass frit under slight vacuum and nitrogen cushion. The solid was dried in a vacuum oven at 40 °C under a reduced pressure of 4 kPa for 16 hours to provide N-ethyl-2-(pyridin-3-yl)thiazol-5-amine dihydrochloride (30.3 g, 98 wt%, 81% yield, 108.8 mmol): 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7 .97(ddd,J=8.3,5.5,0.7Hz,1H),7.54–7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89; ESIMSm / z 206([M+H-2HCl] + ).

[0108] Example 11: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a)

[0109]

[0110] 2-Amino-N-ethylacetamide hydrochloride (4.99 g, 36.0 mmol) and anhydrous ACN (48 mL) were added to a 250-mL jacketed reactor equipped with an overhead stirrer, a nitrogen inlet, a reflux condenser, and a thermocouple under nitrogen. Triethylamine (5.60 mL, 39.7 mmol) was added, and the mixture was stirred for 1 hour to obtain a thick white slurry. Nicotinaldehyde (3.08 g, 28.8 mmol) was added to obtain a thinner slurry. Sulfur solid powder (1.20 g, 37.4 mmol) was added. The mixture was stirred at 70°C and gradually turned into a dark reddish-orange solution. The disappearance of nicotinaldehyde in the reaction was monitored by high performance liquid chromatography (HPLC) (took about 5 hours). The reaction mixture was cooled to 50°C. Phosphorus oxychloride (POCl3, 99%; 6.70 mL, 77.8 mmol) was added dropwise to the reaction mixture while maintaining the internal temperature below 60°C. The dark brown thin slurry / oil was stirred at 50° C. for 7 hours, during which time a yellow slurry formed (monitored by HPLC). The yellow-orange slurry was cooled to 15° C. and toluene (20 mL) was added. The mixture was filtered and the yellow wet cake was dried under vacuum at 40° C. for 16 hours to give the title compound S5a (4.73 g, 58%): 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7 .97(ddd,J=8.3,5.5,0.7Hz,1H),7.54–7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89; ESIMSm / z206([M+H-2HCl] + ).

[0111] Example 12: Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl)

[0112]

[0113] 3-(Methylsulfonyl)propanoic acid (11.1 g, 1.5 eq., 73.1 mmol) was charged to a 250 mL jacketed reactor with the bath temperature set at 25° C., followed by ACN (32.0 g, 779 mmol) and then stirred (internal temperature 23° C.-24° C.). Thionyl chloride (8.69 g, 73.1 mmol) was added dropwise over 1 hour, maintaining the internal temperature <30° C. After the addition was complete, the solution was held at 25° C. for 2 hours (3 hours total) to allow the acid to be converted to the acid chloride, 3-(methylsulfonyl)propanoyl chloride.

[0114] In a separate 250 mL reactor with the bath temperature set at 25° C., N-ethyl-2-(pyridin-3-yl)thiazole-5-amine dihydrochloride (13.5 g, 48.7 mmol) and DCM (33.1 g, 390 mmol) were loaded. Aqueous potassium carbonate (20 wt %, 70.7 g, 102 mmol) was added via a peristaltic pump over 15 minutes. The mixture was stirred at 25° C. for 30 minutes. Stirring was stopped and the phases were separated. The organic layer was reloaded into the 250 mL reactor and the DCM was solvent exchanged with acetonitrile via distillation to produce a solution of S5A-a.

[0115] The solution of 3-(methylsulfonyl)propanoyl chloride S2a was transferred to the solution of S5A-a via a peristaltic pump over 15 minutes, maintaining the internal temperature <30° C. The reaction was stirred at 25° C. for 12 hours, then cooled to 0° C. for another 12 hours before filtering. The wet cake was washed with ACN (50 g), and the solid was dried in a vacuum oven for 18 hours (<50 mm Hg) to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (12.1 g, 66% yield) as a mixture of rotamers: 1 H NMR(400MHz,D2O)δ9.07(m,1H),8.90–8.53(m,2H),8.16–7.91(m,1H),7.6 9(m,1H),4.00–3.56(m,2H),3.52(m,2H),3.24–2.62(m,5H),1.10(m,3H); 13C NMR(101MHz,D2O)δ171.63,169.14,160.98,153.15,143.54,142.70,142.17,141.06,140.03,138.90,137.78,132.5 5,132.38,130.11,128.00,127.95,49.63,49.29,45.99,44.15,40.55,40.36,27.01,26.33,12.05,11.84; ESIMSm / z 340([M+H-HCl] + ).

[0116] Example 13: Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a)

[0117]

[0118] 3-(Methylsulfonyl)propanoic acid (10.5 g, 68.7 mmol) was charged to a 250-mL jacketed reactor with the bath temperature set at 25° C., followed by ACN (30.1 g, mmol) and then stirred (internal temperature 23° C.-24° C.). Thionyl chloride (7.91 g, 66.5 mmol) was added dropwise over 1 hour, maintaining the internal temperature <30° C. The solution was maintained at 25° C. for 2 hours to allow complete conversion to 3-(methylsulfonyl)propanoyl chloride.

[0119] In a separate 250 mL reactor with the bath temperature set at 25° C., N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride S5a (13.4 g, 5.8 mmol) was charged, followed by acetonitrile (60.2 g, 1.47 mol) (internal temperature 24° C.). Triethylamine (9.74 g, 96.2 mmol) was added dropwise via syringe over 5 minutes, and the mixture was aged at 25° C. for 15 minutes. To this was added a solution of 3-(methylsulfonyl)propionyl chloride dropwise over 30 minutes, maintaining the internal temperature at <45° C.

[0120] After 1.5 hours, 20wt% aqueous potassium carbonate solution (87.1g, 126mmol) was added, and the mixture was stirred for 30 minutes. Acetonitrile was removed under vacuum until the overhead product was no longer collected. The resulting mixture was cooled to 0°C within 1 hour and then filtered. The wet cake was washed with water and acetonitrile. The solid was dried in a vacuum oven for 18 hours to obtain N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazole-5-yl)propionamide S6a (13.2g, 81% yield) as a mixture of rotamers: 1H NMR (400MHz, CDCl3) δ9.16–9.12(m,1H),8.75–8.59(m,1H),8.25–8.15(m,1H),7.70–7.61(m,1H) ,7.47–7.34(m,1H),4.09–3.69(m,2H),3.63–3.33(m,2H),3.26–2.76(m,5H),1.52–1.17(m,3H); 13 C NMR (101MHz, CDCl3) δ169.50,167.11,164.92,158.79,151.53,150.36,147.62,147.22,141.95,139.86,137.90,133.56,133. 02,130.14,129.88,129.28,123.87,123.75,50.37,50.15,45.77,44.18,42.08,41.81,27.43,26.55,13.10,12.83; ESIMSm / z 340([M+H] + ]).

[0121] Example 14: Synthesis and Isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a)

[0122]

[0123] N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (29.73 g, 55.5 wt %, 1 eq, 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 metering unit inlet, followed by the addition of ethyl acetate (23.56 g, 267.4 mmol) and the mixture was stirred to provide a white slurry. A 30 wt % aqueous solution of sodium acetate (19.94 g, 72.92 mmol) was added in one portion, followed by acetic acid (4.38 g, 72.92 mmol). A 10 wt % aqueous solution of sodium hypochlorite (45.23 g, 60.76 mmol) was added dropwise over 1 hour. Two hours after the addition was complete, the mixture was quenched with a 32 wt % aqueous solution of sodium thiosulfate (7.205 g, 14.58 mmol). 25wt% sodium hydroxide aqueous solution (3.111g, 19.44mmol) is added dropwise until pH>8. Stop stirring and transfer the organic layer in a 1L round-bottom flask. Under 20kPa vacuum, at 50 ℃ of bath temperatures, the water content in the organic layer is reached to <1wt% via the azeotropic distillation carried out using anhydrous EtOAc. The mixture after the distillation is about 30wt% by mass. The mixture is heated to 70 ℃ and kept for 30 minutes, then cooled to 35 ℃, and spontaneous nucleation occurs now. The mixture is aged 4 hours, and then heptane (26.79g, 267.4mmol) is added dropwise. Finally, the mixture is cooled to 0 ℃ and kept at this temperature for 6 hours. The slurry was filtered, the wet cake was washed with heptane, and the resulting solid was dried in a vacuum oven at 50 °C for 18 hours (<50 mm Hg) to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide S7a (16.2 g, 84% yield) as a beige solid: mp 101-104 °C; 1 H NMR(400MHz, CDCl3) δ9.12(d,J=2.3Hz,1H),8.77–8.71(m,1H),8.22(dt,J=8.1,2.0Hz,1H),7.45(dd,J=8.1,4.8 Hz,1H),3.79(q,J=7.2Hz,2H),3.43(s,2H),2.96(s,3H),2.80(t,J=7.1Hz,2H),1.23(t,J=7.2Hz,3H); ESIMSm / z 374([M+H] + ).

[0124] Example 15: Synthesis and Isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a)

[0125]

[0126] N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide hydrochloride S6a-HCl (15.0 g, 85 wt %, 33.9 mmol) was added to a 250 mL round-bottom flask with a stirring 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 by UPLC at 45 and 75 minutes, showing that approximately 35% of the starting material remained based on the LC area. Another batch of 10 wt % sodium hypochlorite aqueous solution (53.0 g, 71.2 mmol) was added dropwise at 0° C., and the mixture was stirred for another hour. After the reaction was complete, 40 wt % sodium bisulfite aqueous solution (13.2 g, 50.9 mmol) was added dropwise over 30 minutes. 40wt% aqueous potassium carbonate solution (29.3g, 84.8mmol) was added to bring the pH to 10, and the mixture was extracted twice with isopropyl acetate (34.6g, 339mmol). The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The mixture was reconstituted in isopropyl acetate (34.6g, 39.8mL, 339mmol), heated to 70°C to dissolve, and then allowed to cool to room temperature overnight to induce crystallization. The resulting slurry was filtered and washed with cyclohexane (40mL). The solid was dried in a vacuum oven overnight to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (9.5g, 25mmol, 75% yield): mp 101°C-104°C; 1 H NMR(400MHz, CDCl3) δ9.12(d,J=2.3Hz,1H),8.77–8.71(m,1H),8.22(dt,J=8.1,2.0Hz,1H),7.45(dd,J=8.1,4 .8Hz,1H),3.79(q,J=7.2Hz,2H),3.43(s,2H),2.96(s,3H),2.80(t,J=7.1Hz,2H),1.23(t,J=7.2Hz,3H); ESIMS m / z374([M+H] + ).

[0127] Example 16: Synthesis of 2-amino-N-ethylacetamide (S4a)

[0128]

[0129] A solution of ethylamine in water (70wt%, 512g, 7.95mol) was loaded into a jacketed reactor equipped with a mechanical stirrer and a thermocouple under nitrogen, and the reaction mixture was cooled to an internal temperature of -4°C. A solution of glycine methyl ester hydrochloride S3 (200g, 1.58mol) in water (307g) was gradually added to the ethylamine reactor. The temperature was maintained at -3°C, and the reaction mixture was stirred for 1-3 hours. After the reaction was complete, the temperature was raised to 0°C. 50wt% aqueous sodium hydroxide solution (130g, 1.63mol) was added within 10 minutes, and the reaction mixture was stirred for 30 minutes. The reactor was warmed to 95°C to distill out methanol and ethylamine until the volume of the bottoms was stable. The reactor temperature was reduced to 40°C, the pressure was reduced to 10kPa, and distillation was continued by increasing the temperature to 65°C until no ethylamine was detected in the bottoms. The reactor contents were extracted twice with s-BuOH (231g, 3.12mol). In the 4-nitro-2-oxo-1-oxo-4-oxo-5-nitro-2 ...

[0130] Example 17: Synthesis of 2-amino-N-ethylacetamide hydrochloride (S4a-HCl)

[0131]

[0132] In the 5-L jacketed reactor that is equipped with mechanical stirrer and thermocouple under nitrogen, pack into the solution of ethylamine in water (67wt%, 1040g, 15.5mol) and extra water (600g, 33.3mol), and be cooled to internal temperature be-4 ℃.In 4 hours, solid glycine methyl ester hydrochloride S3 (50.49g, 398.13mmol) is added gradually in the ethylamine reactor.The temperature is raised to 0 ℃, and reaction mixture is stirred 2 hours.In 20 minutes, add 48wt% sodium hydroxide aqueous solution (258g, 3.1mol).Reactor is warming up to 80 ℃ to distill out methyl alcohol and ethylamine, until the volume of bottoms is stable.Reactor temperature is reduced to 60 ℃, pressure is reduced to 10kPa, and by being raised to 75 ℃ and continuing distillation, until, in bottoms, do not detect ethylamine. MIBC (1600 g, 15.5 mol) was added and the contents were further distilled at 75 ° C and 8.5-10 kPa to remove water. The slurry was filtered and the solid was washed with MIBC (200 g, 1.94 mol). The filtrates were combined and an aqueous HCl solution (35%, 355 g, 3.41 mol) was added. Another distillation was carried out at 75 ° C and 10 kPa to remove more water. The slurry was cooled to 50 ° C and MTBE (1600 g, 18.0 mol) was added. The slurry was stirred for 30 minutes and cooled to 5 ° C -10 ° C within 90 minutes. The wet cake was filtered and washed twice with MTBE (400 g, 4.49 mol). The wet cake was dried in an oven at 70 ° C for 8 h to give S4a-HCl (389 g, 87.8% yield) as a white solid: mp 136 ° C; 1 H NMR (500MHz, D2O) δ3.71, (s, 2H), 3.19 (q, J = 7.4Hz, 2H), 1.06 (t, J = 7.4Hz, 3H); 13 CNMR(126MHz,D2O)δ166.46,40.48,34.64,13.44.

[0133] Example 18: Extraction of Nicotine Aldehyde

[0134]

[0135] Under stirring, ethyl acetate (102 g) was added to a 250-mL jacketed glass reactor via an addition funnel. An aqueous solution of nicotinaldehyde (16.76 wt % nicotinaldehyde, 102 g) was added to the reactor. Sodium sulfate (Na2SO4, 20 g) was added to the reactor, followed by a commercially available 2.5 M NaOH solution (20 mL). The reactor was heated until the temperature of the reaction mixture reached 41 ° C. The contents were stirred at 270 rpm for 10 minutes. Stirring was stopped and the two layers were allowed to separate and settle. The aqueous and organic layers were collected separately and weighed. (Organic layer - 125.72 g, aqueous layer - 117.93 g) The organic layer was concentrated by rotary evaporation to obtain a viscous liquid. After GC analysis, the viscous layer was found to contain 62.36 wt % nicotinaldehyde.

[0136] Example 19: Extraction of Nicotine Aldehyde

[0137]

[0138] Under stirring, toluene (60g) was added to a 500mL jacketed glass reactor via an addition funnel. An aqueous solution of nicotinaldehyde (18.49wt% nicotinaldehyde, 108.5g) was added to the reactor. Na2SO4 (24g) was added to the reactor, followed by a commercially available 10% NaOH solution (0.32mol equivalent). The reactor was heated until the temperature of the reaction mixture reached 40°C. The contents were stirred at 270rpm for 10 minutes. Stirring was stopped, and the two layers were allowed to separate and settle. The aqueous layer and the organic layer were collected separately, and the aqueous layer was recharged into the reactor. Toluene (60g) was charged into the reactor, and the two phases were stirred at 40°C. Stirring was stopped, and the layers were allowed to settle. The aqueous layer and the organic layer were collected separately, and the two organic layers were combined. The organic layer was analyzed using GC, and it was found that the nicotinaldehyde content in the solution was 13.66wt%.

[0139] Example 20: Synthesis of N-ethyl-2-(pyridine-3-thiocarboxamido)acetamide (S4A-a)

[0140]

[0141] Sulfur (1.32g, 41.1mmol) and S4a-HCl (5.82g, 41.1mmol) are loaded into a 250-mL jacketed reactor equipped with a mechanical stirrer and a thermocouple under nitrogen. Ethyl acetate (38.4g, 42.6mL) is added, followed by triethylamine (4.53g, 44.8mmol) and a 14wt% solution (28.8g) of nicotinaldehyde in ethyl acetate. The suspension is stirred at 350rpm, and heating the mixture to an internal temperature of 67°C. The reaction is maintained under these conditions and monitored by HPLC analysis until completion (18 hours). The reaction mixture is cooled to 50°C. 70% saturated Na2SO4 solution (53.8g, 50.0mL) is added. The reaction mixture is thoroughly mixed at 450rpm for 10 minutes, and allowed to settle for 5 minutes. The water layer is removed. The organic layer is diluted with hot ethyl acetate (31.5g, 30.0mL). 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. A 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 filtered. The wet cake was washed with ethyl acetate (2 x 50.0 mL) and dried in a vacuum oven at 40 ° C under a reduced pressure of 4 kPa to provide the title compound S4A-a (4.36 g, 49% yield) as a yellow solid: mp 145 ° C; 1 H NMR (400MHz, CDCl3) δ9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.3 5(ddd,J=8.0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74; ESIMSm / z 224.2([M+H] + ).

[0142] Example 21: Synthesis of N-ethyl-2-(pyridine-3-thiocarboxamido)acetamide (S4A-a)

[0143]

[0144] Sulfur (1.50 g, 46.7 mmol) and S4a-HCl (6.60 g, 46.7 mmol) were loaded into a 250-mL jacketed reactor equipped with a mechanical stirrer and a thermocouple under nitrogen. Ethyl acetate (62.7 g, 69.5 mL) was added, followed by triethylamine (5.10 g, 50.4 mmol) and nicotinaldehyde (4.00 g). The suspension was stirred at 300 rpm, and it was 67 ° C that the mixture was heated to an internal temperature of 67 ° C. The reaction was maintained under these conditions and monitored by HPLC analysis until completion (18 hours). The reaction mixture was cooled to 50 ° C. 18 wt% saline solution (53.2 g, 50.0 mL) was added. The reaction mixture was fully mixed at 450 rpm for 10 minutes, and then allowed to settle for 5 minutes. The aqueous layer was removed. The organic layer was heated to 60 ° C and stirred at 300 rpm for 1 hour. The solution was slowly cooled to 40 ° C in 3 hours. A seed slurry of S4A-a (0.090 g) in ethyl acetate (1.20 g) was added. The reaction mixture was kept at 40 ° C for 1 hour and cooled to 0 ° C within 7 hours. The resulting slurry was stirred overnight and then filtered. The wet cake was washed with ethyl acetate (3 x 45.0 mL) and dried in a vacuum oven at 40 ° C under a reduced pressure of 4 kPa to provide the title compound S4A-a (5.15 g, 58% yield) as a yellow solid: mp 145 ° C; 1 H NMR (400MHz, CDCl3) δ9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.3 5(ddd,J=8.0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74; ESIMSm / z 224.2([M+H] + ).

[0145] Example 22: Synthesis of N-ethyl-2-(pyridine-3-thiocarboxamido)acetamide (S4A-a)

[0146]

[0147] Into the 500-mL jacketed reactor equipped with mechanical stirrer and thermocouple under nitrogen, 25wt% S4a aqueous solution (104g, 189mmol) and Na2S·9H2O (5.4g, 22.5mmol) are loaded. The pH of the resulting solution is adjusted to 8.79 with 32% HCl solution (10.1g). Sulfur (5.93g, 185mmol) is added, followed by nicotine aldehyde (16.4g, 153mmol) and toluene (128g, 148mL). It is 68°C that the reaction mixture is stirred and heated to an internal temperature of 400rpm. The reaction is maintained under these conditions and monitored by HPLC analysis until completion (19 hours). The reaction mixture is stirred at 85°C, and water (55g, 55mL) is added. The solution is then gradually cooled to 10°C within 4 hours. The slurries are filtered, and the filter cake is washed with water (55mL) and toluene (2x 70mL). The wet cake was dried in a vacuum oven at 90 °C under a reduced pressure of 4 kPa overnight to provide the title compound S4A-a (23.3 g, 69% yield) as a yellow solid: mp 145 °C; 1 H NMR (400MHz, CDCl3) δ9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.3 5(ddd,J=8.0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3) δ195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74. ESIMSm / z 224.2([M+H] + ).

[0148] Example 23: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine (S5A-a)

[0149]

[0150] In 250-mL jacketed reactor, add concentrated sulfuric acid (69.3g, 37.7mL, 95wt%, 10 equivalents, 672mmol). Reactor is cooled to 15 ℃, and in 30 minutes, add N-ethyl-2-(pyridine-3-thiocarboxamido) acetamide S4A-a (15.0g, 1 equivalent, 67.2mmol) in batches, wherein overhead stirring is set to 650rpm and keeps internal temperature lower than 26 ℃ during complete addition. Jacket temperature is set at 40 ℃, and mixture is stirred vigorously (650rpm) 4 hours. Reaction mixture is cooled to ambient temperature and stirred overnight. Reaction mixture is cooled to 10 ℃, and in the situation that temperature never exceeds 25 ℃, water (80mL) is added dropwise in 30 minutes. Then the gained aqueous solution is dropwise processed with 10M KOH aqueous solution in 30 minutes, until reaction mixture thickens and is uneven, and pH is measured to be 7-8. Slurries are discharged in filter funnel and washed with water (2x50mL). The filter cake was dried in a vacuum oven at 50 °C until dry to provide N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine S5A-a (11.72 g, 83% yield): mp 93.67 °C (DSC); 1 H NMR (500MHz, CDCl3) δ8.99(d,J=2.4Hz,1H),8.55(d,J=4.5Hz,1H),8.08(dt,J=8.1,1.9Hz,1H),7. 33(dd,J=8.1,4.8Hz,1H),6.99(s,1H),4.00(s,1H),3.25(q,J=7.2Hz,2H),1.33(t,J=7.1Hz,3H); 13 CNMR(126MHz, CDCl3)δ152.04,149.18,149.13,146.55,132.20,130.47,123.62,121.81,43.06,14.77; ESIMSm / z 206([M+H] + ).

[0151] Example 24: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a)

[0152]

[0153] At 25 ℃-30 ℃, acetonitrile (805.4g, 19.619mol) and S4A-a (145g, 0.6364mol) are added to a jacketed reactor. The mixture is stirred at 500RPM and the reactor is heated to 55 ℃-60 ℃. Phosphorus trichloride (PCl3; 218.49g, 2.50 equivalents, 1.591mol) is added over 2 hours. The temperature is maintained at 60 ℃ for 4-6 hours under stirring. The reaction mixture is cooled to 50 ℃. At 50 ℃ under a vacuum of about 20kPa, acetonitrile and PCl3 are removed by solvent exchange distillation with toluene (1172.7g, 12.728mol). Remove vacuum and the mixture is cooled to 25 ℃. Add water (229.10g, 12.728mol), and at 25 ℃, with 50% potassium carbonate solution (508.7g, 1.840mol), pH is adjusted to 8.0-8.5. The mixture is heated to 50 ℃-55 ℃, and the mixture is stirred for 30 minutes and allowed to settle for 30 minutes. The aqueous layer is separated, and the organic layer is set aside. Toluene (234.5g, 2.546mol) is added to the aqueous layer, and the mixture is stirred for 30 minutes and allowed to settle for 30 minutes. The organic layer is separated. The organic layers are merged, and at 50 ℃-55 ℃, water (229.1g, 12.728mol) is added. The mixture is stirred for 30 minutes and allowed to settle for 30 minutes. The organic layer is separated, and toluene and water are azeotropically distilled at 50 ℃-55 ℃ under a vacuum of about 31kPa. Under reduced pressure, add 400ml of ethyl acetate (200ml, 1.5g, 4.7g, 0.84mmol) and 1.5mol of 4-nitropropene (200ml, 1.5mol) in 1% ethyl acetate (200ml, 1.5mol) and 0.6mmol).Remove vacuum, add fresh toluene (284.2g, 3.084mol) at 50 ℃-55 ℃, and under stirring, the mixture is cooled to 25 ℃-30 ℃.Make anhydrous HCl gas (58.1g, 1.591mol) pass through the mixture at 25 ℃-30 ℃ in 1 hour.Mixture is kept at 25 ℃-30 ℃ for 1 hour.Filter solid, and separate mother liquor.Wet cake is washed with acetonitrile (260.8g, 6.353mol) and allowed to dry 15 minutes under nitrogen atmosphere.Acetonitrile (260.8g, 6.353mol) is added in wet cake, and the mixture is slurried and allowed to dry 15 minutes under nitrogen atmosphere.Wet cake is dried at 40 ℃ under the vacuum of about 6.7kPa. N-Ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (152.4 g, 84% yield) was isolated: 1H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7 .97(ddd,J=8.3,5.5,0.7Hz,1H),7.54–7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89; ESIMSm / z 206([M+H-2HCl] + ).

[0154] Example 25: Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a)

[0155]

[0156] 3-(Methylsulfonyl)propionic acid (3.56 g, 1.2 equivalents, 23.4 mmol) was charged into a 250-mL jacketed reactor with a bath temperature set at 25°C. ACN (24.6 g, 600 mmol) and 3,5-lutidine (1.24 g, 0.59 equivalents, 11.6 mmol) were added. The mixture was stirred. The bath temperature was raised to 35°C. Pivaloyl chloride (3.05 g, 1.3 equivalents, 25.3 mmol) was added. After the addition was complete, the solution was kept at 35°C for 2 hours to allow the acid to be converted into pivalic anhydride, i.e., 3-(methylsulfonyl)propionic acid pivalic anhydride.

[0157] S5A-a was prepared in solution by S5a according to the procedure in Example 12. Dichloromethane was removed by distillation, and the solid was dried under vacuum at 40 ° C for 16 hours to obtain S5A-a (95%) as a yellow solid. Under ambient conditions, S5A-a (4.01g, 1 equivalent, 19.5mmol) was loaded into a 100mL glass reactor. DCM (80.9g, 953mmol) and 3,5-lutidine (2.99g, 1.4 equivalents, 27.9mmol) were added, and the solution was stirred. At 33 ° C, the solution of S5A-a was transferred to a solution of 3- (methylsulfonyl) propionic acid pivalic anhydride. The reaction mixture was stirred at 29 ° C -34 ° C for 19 hours. The mixture was concentrated to 24mL by vacuum distillation at 50 ° C -55 ° C. ACN (31.0 g, 755 mmol) was added, and the mixture was concentrated to 24 mL by vacuum distillation at 55-60 ° C. At 55 ° C, water (24.1 g, 1340 mol) and ACN (6.3 g, 153 mmol) were added to the mixture, and the mixture was concentrated to 24 mL by vacuum distillation at 55-66 ° C. The slurry was cooled to 10 ° C in 4 hours, kept at 10 ° C for 1 hour, and filtered. The wet cake was washed with a 90 / 10 (v / v) mixture of water / ACN (20 mL), and the solid was dried in a vacuum oven at 50 ° C for 16 hours to obtain N- ethyl -3- (methylsulfonyl) -N- (2- (pyridin-3-yl) thiazole -5- bases) propanamide S6a (4.59 g, 68% yield) as a mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ9.16–9.12(m,1H),8.75–8.59(m,1H),8.25–8.15(m,1H),7.70–7.61(m,1H),7.47–7. 34(m,1H),4.09–3.69(m,2H),3.63–3.33(m,2H),3.26–2.76(m,5H),1.52–1.17(m,3H); ESIMSm / z340([M+H] + ]).

[0158] Example 26: Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a)

[0159]

[0160] 3-(Methylsulfonyl)propionic acid (3.55 g, 1.2 equivalents, 23.3 mmol) was loaded into a 250-mL jacketed reactor with a bath temperature set at 25 ° C. DCM (42.2 g, 497 mmol) and 3,5-lutidine (1.25 g, 0.60 equivalents, 11.7 mmol) were added. The mixture was stirred. The bath temperature was raised to 35 ° C. Pivaloyl chloride (3.11 g, 1.3 equivalents, 25.8 mmol) was added. After the addition was complete, the solution was kept at 35 ° C for 2 hours to allow the acid to be converted into pivalic anhydride, i.e., 3-(methylsulfonyl)propionic acid pivalic anhydride (S2a-2).

[0161] S5A-a is prepared in solution by S5a according to the procedure in Example 12. Dichloromethane is removed by distillation, and the solid is dried under vacuum at 40 ° C for 16 hours to obtain S5A-a (95%) as a yellow solid. Under ambient conditions, S5A-a (4.00g, 1 equivalent, 19.5mmol) is loaded into a 100mL glass reactor. DCM (42.2g, 497mmol) and 3,5-lutidine (3.22g, 1.5 equivalents, 30.0mmol) are added, and the solution is stirred. At 35 ° C, the solution of S5A-a is transferred to a solution of 3- (methylsulfonyl) propionic acid pivalic anhydride. The reaction mixture is stirred at 29 ° C -34 ° C for 20 hours. Methanol (31.6g, 989mmol) is added to the mixture, and the mixture is concentrated to 20mL by vacuum distillation. To the 4-thiazolyl-1-yl) propionamide S6a (5.74g, 87% yield) in 4-nitro-2-propanediol (5.70g, 1.79mmol) was added methyl alcohol (31.6g, 989mmol), and the mixture was concentrated to 20mL by vacuum distillation. At 50 ℃, methyl alcohol (15.8g, 494mmol) was added to the mixture. Slurries were cooled to 10 ℃ in 3 hours, kept 1 hour at 10 ℃, and filtered. Wet cake was washed twice with methyl alcohol (15.8g, 494mmol), and solid was dried 16 hours at 50 ℃ in a vacuum drying oven to obtain N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl) thiazole-5-yl) propionamide S6a (5.74g, 87% yield). 1 The H NMR data were consistent with those of S6a.

[0162] Example 27: Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a)

[0163]

[0164] 3-(Methylsulfonyl)propionic acid (913 mg, 1.2 equivalents, 6.00 mmol), acetonitrile (7.86 g, 10.0 mL, 38.3 equivalents, 191 mmol) and pivaloyl chloride (754 mg, 1.25 equivalents, 6.25 mmol) were loaded into a 30 mL vial at 25 ° C. 3-picoline (698 mg, 1.5 equivalents, 7.50 mmol) was added dropwise to prepare a solution of mixed anhydride. The solution was stirred at room temperature for 10-15 minutes. Under ambient conditions, S5a (1.39 g, 1 equivalent, 5.00 mmol) as a yellow solid was loaded into a 40 mL vial. Acetonitrile (7.86 g, 10.0 mL, 38.3 equivalents, 191 mmol) and 3-picoline (1.40 g, 3 equivalents, 15.0 mmol) were slowly added. The suspension is stirred, and at 25 ° C, the solution of the mixed anhydride prepared above is added to the suspension. Reactant is stirred at 50 ° C-55 ° C for 10 hours. The mixture is concentrated to half volume by vacuum distillation, methanol (7.92g, 10.0mL, 49.4 equivalents, 247mmol) is added, and the mixture is re-concentrated to 20mL reaction volume by vacuum distillation. At 25 ° C, methanol (7.92g, 10.0mL, 49.4 equivalents, 247mmol) is added to the mixture. The slurries are cooled to 5 ° C, kept for 1 hour, and then filtered. The wet cake is washed with 5mL methanol-water (1: 1), then washed with water (5mL), and the gained solid is dried at 50 ° C for 16 hours in a vacuum oven to obtain N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazole-5-yl) propionamide (1.53g, 90.2% yield). 1 The H NMR data were consistent with those of S6a.

[0165] Example 28: Synthesis and Isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a)

[0166]

[0167] N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide S6a (30.1 g, 100 wt %, 89 mmol) was added to a 1-L jacketed reactor with an overhead stirrer. Water (157.8 g, 8.8 mol) was added to form a slurry. Aqueous HCl solution (32 wt %, 13.1 g, 122 mmol) was added to the reactor to form a brown solution. The jacket was set to 25 ° C. Chlorine gas (9.1 g, 128 mmol) was slowly added over 50 minutes through a glass tube submerged under the liquid surface. After the reaction was complete, 36 wt % aqueous sodium bisulfite solution (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 solution (50 wt %, 25.5 g, 319 mmol) was added to bring the pH to 7. The reactor was warmed to 35 ° C. At 4 DEG C, 1H-dextrose (5-nitro-2-nitro-1-propane) (25.4g, 76% yield) was added to the 4-chloro-2-(pyridin-3-yl)thiazole-5-yl)-N-ethyl-3-(methylsulfonyl) propionamide (25.4g, 76% yield) of 4-chloro-2-(pyridin-3-yl)thiazole-5-yl)-N-ethyl-3-(methylsulfonyl) propionamide.The mixture was kept at 30 DEG C for 2 hours.Then, the mixture was added dropwise at 2 hours. The slurries were cooled to -10 DEG C in 1 hour, and kept for another 1 hour, then filtered. The wet cake was washed once with heptane (44.8g, 447mmol). The solid was dried in a vacuum oven overnight to obtain N-(4-chloro-2-(pyridin-3-yl)thiazole-5-yl)-N-ethyl-3-(methylsulfonyl) propionamide (25.4g, 76% yield).

[0168] Example 29: Synthesis of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a)

[0169]

[0170] N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (12.50 g, 85 wt%, 1 eq, 28.27 mmol) was added to a 250 mL jacketed reactor followed by water (37.69 g, 37.69 mL, 74 eq, 2.092 mol). The mixture was stirred at 23°C. Separately prepared in a round bottom flask under stirring (20.85 g, 1.2 eq., 33.92 mmol) in water (63.67 g, 63.67 mL, 125 eq., 3.533 mol) (pH about 2.5). The solution of 4-nitropropene (2-nitropropene) was added dropwise to a jacketed reactor, and the mixture was stirred. After complete conversion was observed, sodium bisulfite (8.823 g, 40 wt %, 1.2 eq., 33.92 mmol) was added dropwise over 15 minutes. Potassium carbonate (23.44 g, 20 wt %, 1.2 eq., 33.92 mmol) was added dropwise to bring the pH to 10. Isobutyl acetate (32.83 g, 41.8 mL, 10 eq., 282.7 mmol) was added in one 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 eq., 282.7 mmol) was added in one 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 placed under vacuum at 50° C. to concentrate the mixture to <1.0 wt % water via azeotropy. After reaching the desired amount of water, the mixture is heated to 65°C-70°C to dissolve all materials, and then allowed to cool to 0°C over 12 hours. The mixture is kept for 4 hours and then filtered. The wet cake is washed with 50 mL of heptane and dried in a vacuum oven (50°C, <50 mm Hg) to obtain N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (8.5 g, 71% yield).

[0171] Therefore, in view of the above, the following additional non-exhaustive disclosure details (d) are provided.

[0172] 1d. A method comprising:

[0173]

[0174] 3-(Methylthio)propionic acid is oxidized to 3-(methylsulfonyl)propionic acid in the presence of an oxidizing agent and a polar solvent.

[0175] 2d. The method according to detail 1d, wherein the oxidizing agent is oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), an organic peroxide, an organic peracid (-OOH), potassium peroxymonosulfate, potassium persulfate, potassium peroxymonosulfate sulfate (a triple salt having the formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8]), or a mixture thereof.

[0176] 3d. The method according to detail 1d, wherein the oxidizing agent hydrogen peroxide (H2O2) further comprises a catalyst sodium tungstate.

[0177] 4d. The method according to details 1d, 2d, and 3d, wherein about 2 moles to about 4 moles of oxidant per mole of S1a are used.

[0178] 5d. The method of details 1d, 2d, and 3d, wherein about 2.0 moles to about 3.0 moles of oxidant per mole of S1a is used.

[0179] 6d. The method according to details 1d, 2d, 3d, 4d, and 5d, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof.

[0180] 7d. The method according to detail 6d, wherein the solvent is ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), dichloromethane ("DCM"), acetone, acetonitrile ("ACN"), N,N-dimethylformamide ("DMF"), dimethyl sulfoxide ("DMSO"), acetic acid ("AcOH"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), formic acid ("HCOOH"), tert-butanol ("t-BuOH"), water ("H2O"), or a mixture thereof.

[0181] 8d. The method according to details 1d, 2d, 3d, 4d, 5d, 6d, and 7d, wherein the oxidation is carried out at a temperature of about 15° C. to about 25° C. and a pressure of about 95 kPa to about 105 kPa.

[0182] 9d. A method comprising reacting S1b in the presence of a carboxylic acid activating agent and an aprotic solvent to produce S2a

[0183]

[0184] wherein A is Cl, O(C=O)R1, or OR1, wherein R1 is (C1-C4)alkyl, and wherein the reaction is optionally carried out with a catalyst or a base to promote the reaction of S1b to S2a.

[0185] 10d. The method of detail 9d, wherein from about 1.0 mole to about 5 moles of the carboxylic acid activating agent per mole of S1b is used.

[0186] 11d. The method of detail 9d, wherein about 1.0 mole to about 1.5 moles of the carboxylic acid activating agent per mole of S1b is used.

[0187] 12d. The method according to details 9d, 10d, and 11d, wherein a catalyst is used to promote the reaction of S1b to S2a.

[0188] 13d. The method according to detail 12d, wherein the catalyst is N,N-dimethylformamide, N-formylpyrrolidine, N-formylpiperidine, or a mixture thereof.

[0189] 14d. The method according to details 12d and 13d, wherein about 0.01 to about 0.5 mol of catalyst per mol of S1b is used.

[0190] 15d. The method according to details 12d and 13d, wherein about 0.05 mol to about 0.1 mol of catalyst per mol of S1b is used.

[0191] 16d. The method according to details 9d, 10d, and 11d, wherein a base is used to promote the reaction of S1b to S2a.

[0192] 17d. The method according to detail 16d, wherein the base is lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N-methylmorpholine, triethylamine ("TEA"), N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof.

[0193] 18d. The method according to details 16d and 17d, wherein about 0.1 to about 1.5 mol of base per mol of S1b is used.

[0194] 19d. The method according to details 16d and 17d, wherein about 0.5 mol to about 1.2 mol of base per mol of S1b is used.

[0195] 20d. The method according to details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, and 19d, wherein the aprotic solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof.

[0196] 21d. The method according to detail 20d, wherein the solvent is ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), acetonitrile ("ACN"), benzonitrile ("PhCN"), chloroform ("CHCl3"), toluene ("PhCH3"), or a mixture thereof.

[0197] 22d. The method according to details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, and 21d, wherein the temperature of the reaction is about 0°C to about 100°C.

[0198] 23d. The method according to details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 20d, and 21d, wherein the temperature of the reaction is about 20°C to about 60°C.

[0199] 24d. The method according to details 9d, 10d, 11d, 16d, 17d, 18d, 19d, 20d, and 21d, wherein the temperature of the reaction is about 20°C to about 49°C.

[0200] 25d. The method according to details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, 21d, 22d, 23d, and 24d, wherein S2a is separated or used directly under flow conditions without separation.

[0201] 26d. A method comprising aminating S3 / 3a to S4a or S4a-HCl with ethylamine in the presence of a secondary base and optionally a polar or non-polar solvent,

[0202]

[0203] 27d. The method according to detail 26d, wherein the amount of ethylamine used is about 1 mole to about 15 moles of ethylamine per mole of S3 / 3a.

[0204] 28d. The method according to detail 26d, wherein the amount of ethylamine used is about 5 mol to about 12 mol of ethylamine per mol of S3 / 3a.

[0205] 29d. The method according to any one of the preceding details 26d to 28d, wherein the secondary base is an organic base.

[0206] 30d. The method according to any one of the preceding details 26d to 28d, wherein the secondary base is an inorganic base.

[0207] 31d. The method according to any one of the preceding details 26d to 28d, wherein the secondary base is N,N-diisopropylethylamine or triethylamine.

[0208] 32d. The method according to any one of the preceding details 26d to 28d, wherein the secondary base is potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, or a mixture thereof.

[0209] 33d. The process according to any one of the preceding details 26d to 32d, wherein the amount used is from about 0.8 mol to about 2 mol of the secondary base per mol of S3 / 3a.

[0210] 34d. The process according to any one of the preceding details 26d to 32d, wherein the amount used is from about 0.8 mol to about 1.2 mol of the secondary base per mol of S3 / 3a.

[0211] 35d. The method according to any one of the preceding details 26d to 34d, wherein the polar solvent is a polar aprotic solvent.

[0212] 36d. The method according to any one of the preceding details 26d to 34d, wherein the polar solvent is a polar protic solvent.

[0213] 37d. The method according to any one of the preceding details 26d to 34d, wherein the polar solvent is tetrahydrofuran, 2-methyltetrahydrofuran, anisole, acetonitrile, or a mixture thereof.

[0214] 38d. The method according to any one of the preceding details 26d to 34d, wherein the polar solvent is n-butanol, sec-butanol, 4-methyl-2-pentanol, isopropanol, n-propanol, ethanol, methanol, water, or a mixture thereof.

[0215] 39d. The method according to any one of the preceding details 26d to 34d, wherein the non-polar solvent is toluene.

[0216] 40d. The method according to any one of the preceding details 26d to 39d, wherein the method is carried out at a temperature of about -20°C to about 50°C.

[0217] 41d. The method according to any one of the preceding details 26d to 39d, wherein the method is carried out at a temperature of about -10°C to about 10°C.

[0218] 42d. The method according to any one of the preceding details 26d to 41d, wherein the method is carried out at a pressure of about 10 kPa to about 1000 kPa or about ambient pressure to about 1000 kPa.

[0219] 43d. The method according to any one of the preceding details 26d to 41d, wherein the method is carried out at a pressure of about 50 kPa to about 200 kPa or about ambient pressure to about 200 kPa.

[0220] 44d. The method according to any one of the preceding details 26d to 43d, wherein the method is carried out under continuous flow conditions.

[0221] 45d. A method according to any one of the preceding details 26d to 44d, wherein S4a

[0222] (a) isolated as a free base;

[0223] (b) used as the free base in solution; or

[0224] (c) Isolated as the hydrochloride salt.

[0225] 46d. A method comprising reacting S4a or S4a-HCl with 3-pyridinecarboxaldehyde in the presence of sulfur, a Bronsted base and a solvent to produce S4A-a

[0226]

[0227] 47d. The method according to detail 46d, wherein the 3-pyridinecarboxaldehyde is used in pure form, as a solution in water, or as a solution in an organic solvent.

[0228] 48d. The method according to details 46d and 47d, wherein about 0.5 mol to about 5 mol of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

[0229] 49d. The method according to details 46d and 47d, wherein about 0.7 mol to about 1.3 mol of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

[0230] 50d. The method of details 46d, 47d, 48d, and 49d, wherein about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl is used.

[0231] 51d. The method of details 46d, 47d, 48d, and 49d, wherein about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl is used.

[0232] 52d. The method according to details 46d, 47d, 48d, 49d, 50d, and 51d, wherein 0.05 mol to about 5 mol of Bronsted base per mol of S4a or S4a-HCl is used.

[0233] 53d. The method of details 46d, 47d, 48d, 49d, 50d, and 51d, wherein about 0.1 mol to about 1.2 mol of Bronsted base per mol of S4a or S4a-HCl is used.

[0234] 54d. The method according to details 46d, 47d, 48d, 49d, 50d, 51d, 52d, and 53d, wherein the Bronsted base is potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof.

[0235] 55d. The method according to details 46d, 47d, 48d, 49d, 50d, 51d, 52d, and 53d, wherein the Bronsted base is sodium sulfide ("Na2S") or triethylamine ("TEA").

[0236] 56d. The method according to details 46d, 47d, 48d, 49d, 50d, 51d, 52d, 53d, 54d, and 55d, wherein the solvent is a polar aprotic solvent, a polar protic solvent, a non-polar aprotic solvent, or a mixture thereof.

[0237] 57d. The method according to detail 56d, wherein the solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), butyronitrile, cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), ethyl acetate ("EtOAc"), isopropyl acetate ("i-PrOAc"), N,N-dimethylformamide ("DMF"), N,N-dimethylacetamide ("DMAC"), acetic acid isobutyl ether ("i-BuOAc"), methyl ethyl ketone ("MEK"), dichloromethane ("DCM"), chlorobenzene ("PhCl"), acetone, n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropyl alcohol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H2O"), toluene ("PhCH3"), or mixtures thereof.

[0238] 58d. The method according to any one of the preceding details 46d to 57d, wherein the temperature at which the reaction is carried out is from about -10°C to about 100°C.

[0239] 59d. The method according to any one of the preceding details 46d to 57d, wherein the temperature at which the reaction is carried out is about 35°C to 70°C.

[0240] 60d. The method according to any one of the preceding details 46d to 59d, wherein the reaction is carried out at a pressure of ambient pressure to 1000 kilopascals (kPa).

[0241] 61d. A method according to any one of the preceding details 46d to 59d, wherein the pressure at which the reaction is carried out is from ambient pressure to about 200 kPa.

[0242] 62d. The method according to any one of the preceding details 46d to 61d, wherein the pH at which the reaction is carried out is 6 to 13.

[0243] 63d. The method according to any one of the preceding details 46d to 61d, wherein the pH at which the reaction is carried out is 8 to 10.

[0244] 64d. A method comprising converting S4A-a into S5a in the presence of a Lewis acid or a Bronsted acid

[0245]

[0246] Optionally, the conversion is carried out in the presence of a solvent.

[0247] 65d. The method according to detail 64d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), 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 ("HBr in water"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("H2SO4"), a solid supported acidic resin, or a mixture thereof.

[0248] 66d. The method according to detail 65d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride ("POCl3") or phosphorus trichloride ("PCl3").

[0249] 67d. The method according to detail 65d, wherein the Lewis acid or Bronsted acid is sulfuric acid.

[0250] 68d. The method of details 64d, 65d, 66d, and 67d, wherein about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mole of S4a is used.

[0251] 69d. The method of details 64d, 65d, 66d, and 67d, wherein about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4a is used.

[0252] 70d. The method according to details 64d, 65d, 66d, 67d, 68d, and 69d, wherein the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof.

[0253] 71d. The method according to detail 70d, wherein the solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), and ethyl acetate ("EtOAc"), toluene ("PhCH3"), chlorobenzene ("PhCl") or a mixture thereof.

[0254] 72d. The method according to detail 71d, wherein the solvent is acetonitrile.

[0255] 73d. The method according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, and 72d, wherein the temperature at which the conversion is carried out is about -10°C to about 80°C.

[0256] 74d. The method according to detail 73d, wherein the temperature is about 45°C to 75°C.

[0257] 75d. The method according to detail 73d, wherein the temperature is about 10°C to 44°C.

[0258] 76d. The method of details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 72d, 72d, 74d, 74d, and 75d, wherein the pressure at which the conversion is carried out is from ambient pressure to about 1000 kilopascals (kPa).

[0259] 77d. The method of detail 76d, wherein the pressure is ambient pressure to about 200 kPa.

[0260] 78d. The method according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, and 77d, wherein the conversion is carried out under flow conditions.

[0261] 79d. The method of details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, 77, and 78d, wherein S5a is isolated as the free amine S5A-a.

[0262] 80d. The method according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, 77, and 78d, wherein the free amine S5A-a can be converted into the salt form S5a.

[0263] 81d. A method comprising reacting S4a or S4a-HCl to produce S5a, wherein the reaction is carried out in the presence of 3-pyridinecarboxaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid,

[0264]

[0265] Optionally, this reaction is carried out in a solvent.

[0266] 82d. The method according to detail 81d, wherein the 3-pyridinecarboxaldehyde is used in pure form, as a solution in water, or as a solution in an organic solvent.

[0267] 83d. The method of details 81d and 82d, wherein about 0.5 mol to about 5 mol of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

[0268] 84d. The method according to details 81d and 82d, wherein about 0.7 mol to about 1.3 mol of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

[0269] 85d. The method of details 81d, 82d, 83d, and 84d, wherein about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl is used.

[0270] 86d. The method of details 81d, 82d, 83d, and 84d, wherein about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl is used.

[0271] 87d. The method of details 81d, 82d, 83d, 84d, 85d, and 86d, wherein from about 0.05 mole to about 5 moles of Bronsted base per mole of S4a or S4a-HCl is used.

[0272] 88d. The method of details 81d, 82d, 83d, 84d, 85d, and 86d, wherein about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl is used.

[0273] 89d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, and 88d, wherein about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCl is used.

[0274] 90d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, and 88d, wherein about 1 to about 5 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCl is used.

[0275] 91d. The method according to details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, and 90d, wherein the Bronsted base is potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof.

[0276] 92d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, and 90d, wherein the Bronsted base is sodium sulfide ("Na2S") or triethylamine ("TEA").

[0277] 93d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d and 92d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), boron trifluoride diethyl etherate ("BF3.OEt2"), trimethylsilyl 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-toluenesulfonic acid ("p-TSA"), sulfuric acid ("H2SO4"), a solid supported acidic resin, or a mixture thereof.

[0278] 94d. The method according to detail 93d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride or phosphorus trichloride.

[0279] 95d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, and 94d, wherein a solvent is used and the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof.

[0280] 96d. The method according to detail 95d, wherein the solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), ethyl acetate ("EtOAc"), toluene ("PhCH3"), or a mixture thereof.

[0281] 97d. The method according to detail 96d, wherein the solvent is acetonitrile.

[0282] 98d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, and 97d, wherein the reaction is carried out at a temperature of about -10°C to about 80°C.

[0283] 99d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, and 97d, wherein the reaction is carried out at a temperature of about 35°C to about 70°C.

[0284] 100d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, 97d, 98d, and 99d, wherein the reaction is carried out at a pressure of about ambient pressure to 1000 kilopascals (kPa).

[0285] 101d. The method of detail 100d, wherein the pressure is ambient pressure to about 200 kPa.

[0286] 102d. The method according to any one of the preceding details 81d to 101d, wherein the reaction is carried out under flow conditions.

[0287] 103d. A method comprising coupling S5a with S2a to produce S6a or S6a-HCl, wherein the coupling is carried out in the presence of a base, a solvent and optionally a catalyst.

[0288]

[0289] 104d. The method according to detail 103d, wherein the base is an organic base, an inorganic base, or a mixture thereof.

[0290] 105d. The method according to detail 103d, wherein the base is an organic base.

[0291] 106d. The method according to detail 103d, wherein the base is an inorganic base.

[0292] 107d. The method according to details 103d, 104d, 105d, and 106d, wherein the base is pyridine, lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N,N-diisopropylethylamine ("DIPEA"), triethylamine ("TEA"), potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3"), sodium hydroxide ("NaOH"), or a mixture thereof.

[0293] 108d. The method of details 103d, 104d, 105d, 106d, and 107d, wherein about 1 mole to about 5 moles of base per mole of S5a is used.

[0294] 109d. The method of detail 108d, wherein about 2.0 moles to about 3.5 moles of base per mole of S5a is used.

[0295] 110d. The method according to details 103d, 104d, 105d, 106d, 107d, 108d, and 109d, wherein the catalyst is N,N-dimethylpyridin-4-amine ("DMAP"), N-methylimidazole ("NMI"), or a mixture thereof.

[0296] 111d. The method according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, and 110d, wherein the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof.

[0297] 112d. The method according to detail 111d, wherein the solvent is ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl3"), acetonitrile ("ACN"), benzonitrile ("PhCN"), toluene ("PhCH3"), or a mixture thereof.

[0298] 113d. The method according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, 110d, 111d, and 112d, wherein the coupling is carried out at a temperature of about -10°C to about 80°C.

[0299] 114d. The method of detail 113d, wherein the temperature is about 0°C to 60°C.

[0300] 115d. The method according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, 110d, 111d, 112d, 113d, and 114d, wherein the coupling is carried out at a pressure of ambient pressure to 1000 kilopascals (kPa).

[0301] 116d. The method of detail 115d, wherein the pressure is ambient pressure to about 200 kPa.

[0302] 117d. A method according to any one of the preceding details 103d to 116d, wherein S6a

[0303] (a) isolated as a free base;

[0304] (b) as the hydrochloride salt (S6a-HCl) or hydrobromide salt in solution; or

[0305] (c) Isolated as the hydrochloride salt (S6a-HCl) or the hydrobromide salt.

[0306] 118d. A method comprising

[0307] Chlorination with a chlorinating agent in the presence of a polar solvent

[0308] (a) N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide (S6a) and / or

[0309] (b) N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl);

[0310] To produce N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a)

[0311]

[0312] 119d. The method of detail 118d, wherein about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

[0313] 120d. The method of detail 118d, wherein about 1.0 mole to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

[0314] 121d. The method according to details 118d, 119d, and 120d, wherein the chlorinating agent is chlorine, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), sodium hypochlorite, or a mixture thereof.

[0315] 122d. The method according to detail 121d, wherein the chlorinating agent is sodium hypochlorite.

[0316] 123d. The method according to detail 121d, wherein the chlorinating agent is chlorine gas.

[0317] 124d. A method according to details 118d, 119d, and 120d, wherein the chlorination comprises contacting S6a-HCl with an oxidizing agent, preferably potassium peroxymonosulfate sulfate (a triple salt having the formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8]).

[0318] 125d. The method of detail 124d, wherein the chlorination further comprises adding a chloride salt or hydrochloric acid.

[0319] 126d. The method according to details 118d, 119d, 120d, 121d, 122d, 123d, 124d, and 125d, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof.

[0320] 127d. The method according to detail 126d, wherein the solvent is 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H2O"), acetic acid ("AcOH"), formic acid ("HCOOH"), hydrochloric acid ("HCl") aqueous solution, or a mixture thereof.

[0321] 128d. The method according to detail 127d, wherein the solvent is ethyl acetate.

[0322] 129d. The method according to detail 127d, wherein the solvent is acetic acid.

[0323] 130d. The method according to detail 1273d, wherein the solvent is aqueous hydrochloric acid.

[0324] 131d. The method of details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, and 130d, wherein the chlorination is carried out at a temperature of about -10°C to about 80°C.

[0325] 132d. The method of detail 131d, wherein the temperature is about 0°C to 50°C.

[0326] 133d. The method of details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, 130d, 131d, and 132d, wherein the chlorination is carried out at a pressure from ambient pressure to about 1000 kilopascals (kPa).

[0327] 134d. The method according to detail 133d, wherein the chlorination is carried out at a pressure from ambient pressure to about 200 kPa.

[0328] 135d. A molecule of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide

[0329]

[0330] 136d. A composition comprising a molecule according to detail 135d and HCl.

Claims

1. One molecule N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propionamide (S6a) or an agriculturally acceptable acid addition salt thereof having the formula 2. The molecule according to claim 1, wherein The agriculturally acceptable acid addition salt is the hydrochloride (S6a-HCl) and has the formula 3. A method comprising: (a) coupling S5a with S2a to produce the molecule according to claim 1 (S6a) or the molecule according to claim 2 (S6a-HCl), wherein the coupling is carried out in the presence of a base, a solvent, and optionally a catalyst as well as (b) Chlorination with a chlorinating agent in the presence of a polar solvent (a) the molecule (S6a) according to claim 1 and / or (b) the molecule (S6a-HCl) according to claim 2, To produce N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propionamide (S7a) 4. The method according to claim 3, wherein: From about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl are used.

5. The method according to claim 3, wherein From about 1.0 mole to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl are used.

6. The method according to claim 3, 4 or 5, wherein: The chlorinating agent is chlorine gas, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), sodium hypochlorite, or a mixture thereof.

7. The method according to claim 6, wherein: The chlorinating agent is sodium hypochlorite.

8. The method according to claim 6, wherein: The chlorinating agent is chlorine gas.

9. The method according to claim 3, 4 or 5, wherein: The chlorination comprises contacting the molecule (S6a-HCl) according to claim 2 with an oxidizing agent, preferably potassium peroxymonosulfate sulfate (a triple salt having the formula 2KHSO5.KHSO4.K2SO4 [CAS 70693-62-8]).

10. The method according to claim 9, wherein: The chlorination further comprises adding a chloride salt or hydrochloric acid.

11. The method of claim 3, 4, 5, 6, 7, 8, 9, or 10, wherein: The polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof.

12. The method according to claim 11, wherein The solvent is 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H2O"), acetic acid ("AcOH"), aqueous hydrochloric acid solution or a mixture thereof.

13. The method according to claim 10, wherein: The solvent is ethyl acetate, aqueous hydrochloric acid, or acetic acid.

14. The method of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein The chlorination is carried out at a temperature of about -10°C to about 80°C or about 0°C to 50°C.

15. The method of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein The chlorination is conducted at a pressure of from ambient pressure to about 1000 kilopascals (kPa) or from ambient pressure to about 200 kPa.

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