Processes related to formation of n-ethyl-2-(pyridin-3-YL)thiazol-5-amine

Abstract

A molecule, N-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3), having the following formula, is provided. Processes to make and use a molecule of S3 are also provided.

Description

212574-US-PRV-lPROCESSES RELATED TO FORMATION OF A-ETHYL-2-(PYRIDIN-3-YL)THIAZOL-5-AMINECROSS REFERENCE TO RELATED TO APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.63 / 680,256 filed August 7, 2024, which is expressly incorporated by reference herein.BACKGROUND

[0002] Preparation of 2-(pyri din-3 -yl)thiazoles has been disclosed in applications WO 2010 / 129497; WO 2013 / 184475; WO 2013 / 184476; WO 2013 / 184480; and WO 2023 / 015135.SUMMARY

[0003] A molecule, A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3), having the following formula is provided.

[0004] Processes to make and use a molecule of S3 are provided. Additionally, processes related to the formation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4) or salts thereof are provided. Examples of salts include the salts of methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, and phosphoric acid. The molecule S3 may be useful in the process to prepare V-(4-chloro-2-(pyri din-3 -yl)thiazol-5-yl)-A- ethyl-3-(methylsulfonyl)propanamide.212574-US-PRV-l2DETAILED DESCRIPTION

[0005] A molecule, A-(2-(ethylamino)-2-thioxoethyl)ni cotinamide (also known as “S3” herein), is provided.

[0006] Additionally, processes to make and use a molecule of S3 are provided. The molecule S3 may be useful in the process to prepare A-cthyl-2-(pyridin-3-yl)thiazol-5-amine (S4) or salts thereof.

[0007] The following are processes related to the formation of 7V-ethyl-2-(pyridin-3- yl)thiazol-5 -amine (also known as “S4” herein) or salts thereof, shown below. The molecule S4 may be useful in the process to prepare A,-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3- (methylsulfonyl)propanamide.

[0008] Definitions

[0009] It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. These definitions are only to be used for the purposes of this disclosure.

[0010] The term “ambient pressure” refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.

[0011] The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.

[0012] The term “catalyst” refers to any substance that increases the rate of a reaction without itself being consumed.

[0013] The term “telescope process” or “telescopic reaction” means a type of synthesis that subjects a reactant or reactants to successive chemical reactions in a sequential order in just one reactor.212574-US-PRV-l

[0014] Scheme OneS1 S2 wherein X1is OH (Sla) or Cl (Sib) or a hydrochloride salt thereof (»HC1, Slb-HCl).

[0015] In one embodiment, the reaction in Scheme One is an amide coupling of nicotinoyl chloride (also known as “Sib” herein, X1= Cl) or nicotinoyl chloride hydrochloride (also known as “Slb-HCl” herein, X1= Cl) and 2-aminoacetonitrile or 2-aminoacetonitrile hydrochloride to provide A-(cyanomethyl)nicotinamide (also known as “S2” herein) or N- (cyanomethyl)nicotinamide hydrochloride (also known as “S2-HC1” herein).

[0016] The reaction in Scheme One is conducted in the presence of a base. Examples of bases are organic bases and inorganic bases. Examples of organic bases are pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, 5-ethyl-2-methylpyridine, A(7V-diisopropylethylamine (“DIPEA”), N- methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, and triethylamine (“EtsN”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), and sodium bicarbonate (“NaHCOs”). Mixtures of bases may also be used.

[0017] In some aspects, the reaction in Scheme One may produce the desired product, S2 or S2-HC1, when appropriate equivalents of base are used, respectively.

[0018] The reaction in Scheme One is conducted in the presence of a polar or a nonpolar solvent. Examples of solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), di chloromethane ("DCM”), 1,2-dichloroethane, chlorobenzene (“PhCl”), 1,2-dichlorobenzene, and toluene (“PhCH ’). Optionally, mixtures of solvents may be used.

[0019] The reaction in Scheme One may be conducted at temperatures from about -10 °C to about 25 °C, and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.212574-US-PRV-l4

[0020] Alternatively, the reaction in Scheme One is an amide coupling of nicotinoyl chloride (also known as “Sib” herein, X1= Cl) and 2-aminoacetonitrile hydrochloride. Nicotinoyl chloride (Sib) may be generated in situ from nicotinic acid (also known as “Sla” herein, X1= OH), a carboxylic acid activator, a base, a solvent, and optionally a catalyst. Examples of carboxylic acid activators include thionyl chloride, oxalyl chloride, and pivaloyl chloride. In general, from about 0.9 moles to about 1.3 moles of carboxylic acid activator per mole of Sla may be used; preferably, from about 1.0 moles to about 1.2 moles of carboxylic acid activator per mole of Sla may be used.

[0021] Examples of bases are organic bases and inorganic bases. Examples of organic bases are pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2- methylpyridine, 3 -methyl pyridine, 5 -ethyl -2-methylpyri dine, Af,,V-diisopropylethylamine (“DIPEA”), A-methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, and triethylamine (“EtsN”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), and sodium bicarbonate (“NaHCCh”). In general, from about 0.9 moles to about 1.3 moles of base per mole of Sla may be used; preferably, from about 1 .0 moles to about 1 .2 moles of base per mole of Sla may be used. Mixtures of bases may also be used.

[0022] Examples of solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), di chloromethane ("DCM”), 1,2-di chloroethane, chlorobenzene (“PhCl”), 1,2-dichlorobenzene, and toluene (“PI1CH3”). Optionally, mixtures of solvents may be used.

[0023] Examples of optional catalysts are M / V-dimethylformamide (“DMF”) and piperidine- 1-carbaldehyde. In general, from about 0.001 to about 0.01 moles of catalyst per mole of Sla may be used; preferably, from about 0.0025 moles to about 0.0075 moles of catalyst per mole of Sla may be used.

[0024] The reaction may be conducted at temperatures from about -10 °C to about 25 °C, and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0025] The molecule S2 or salt thereof may be isolated and used or used without isolation from the solvent in a telescoped manner in the subsequent reaction.212574-US-PRV-l5

[0026] Scheme TwoS2 S3

[0027] The reaction in Scheme Two is conducted in the presence of a thiolation reagent and ethylamine or a salt thereof, whereby S2 or a salt thereof is converted to A-(2-ethylamino)-2- thioxoethyl)nicotinamide (also known as “S3” herein).

[0028] The reaction in Scheme Two is conducted in the presence of a thiolation reagent. Examples of thiolation reagents are sodium hydrogen sulfide or hydrate thereof, sodium sulfide, ammonium sulfide, hydrogen sulfide, and pre-formed ethylamine-hydrogen sulfide salt. In general, from about 1 mole to about 5 moles of thiolation reagent per mole of S2 may be used; preferably, from about 1.3 moles to about 3.5 moles of thiolation reagent per mole of S2 may be used.

[0029] The reaction in Scheme Two is conducted in the presence of ethylamine or a salt thereof. An example of a salt is the hydrochloride salt, ethanamine hydrochloride. In general, from about 1 mole to about 5 moles of ethylamine or ethanamine hydrochloride per mole of S2 may be used; preferably, from about 1.3 moles to about 3.5 moles of ethylamine or ethanamine hydrochloride per mole of S2 may be used.

[0030] The reaction in Scheme Two is conducted in the presence of a polar aprotic or a polar protic solvent. Examples of polar aprotic solvents are tetrahydrofuran (“THF”), acetonitrile, chlorobenzene (“PhQ”), and dichloromethane (“DCM”). Examples of polar protic solvents are methanol (“MeOH”), ethanol (“EtOH”), isopropyl alcohol (z-PrOH), and water. Optionally, mixtures of solvents may be used.

[0031] The reaction in Scheme Two may be conducted at temperatures from about 0 °C to about 50 °C and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0032] The molecule S3 may be isolated and used or used without isolation from the solvent in a telescoped manner in the subsequent reaction.212574-US-PRV-l

[0033] Scheme Three

[0034] The reaction in Scheme Three is conducted in the presence of a Lewis or Bronsted acid, whereby S3 is transformed into A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (also known as “S4” herein) or salts thereof. Examples of Lewis or Bron st ed acids are sulfuric acid (“H2SO4”), fuming sulfuric acid (“H2SO4 + SO3”), phosphorus trichloride (“PCI3”), phosphorus oxychloride (“POCI3”), polyphosphoric acid, methanesulfonic acid (“MsOH”), trifluoromethanesulfonic acid (“TfOH”), anhydrous / 2-toluenesulfonic acid, and benzenesulfonic acid. In general, from about 1.5 moles to about 25 moles of Lewis or Bronsted acid per mole of S3 may be used; preferably, from about 2.5 moles to about 15 moles of Lewis or Bronsted acid per mole of S3 may be used. Methanesulfonic acid (“MsOH”) is preferred.

[0035] The reaction in Scheme Three may also be conducted in the presence of a solvent. Examples of solvents are chlorobenzene (“PhCl”), sulfolane, dimethyl carbonate, 1,4-di oxane, propylene carbonate, acetonitrile (“ACN”), benzonitrile, di chlorobenzene, dichloromethane ("DCM”), and toluene (“PhCHf’). Bronsted acids such as tri fluoroacetic acid (“TFA”) or trichloroacetic acid (“TCA”) may be used as solvents when fuming sulfuric acid is used. Optionally, mixtures of solvents may be used.

[0036] The reaction in Scheme Three may be conducted at temperatures from about 20 °C to about 120 °C and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0037] In another embodiment, the reactions in Scheme One through Scheme 3 may be done as a telescope process.

[0038] Examples provided herein are not exhaustive and should not be construed as limiting.EXAMPLE 1

[0039] Preparation of A-(cyanomethyl)nicotinamide (S2) from nicotinoyl chloride hydrochloride212574-US-PRV-l7S1b-HCI S2

[0040] To a 25 milliliter (mL) vial with a stir bar were added sequentially nicotinoyl chloride hydrochloride (1.00 gram (g), 1 equivalent (equiv), 5.62 millimoles (mmol)), 2-aminoacetonitrile hydrochloride (624 milligrams (mg), 1.2 equiv, 6.74 mmol), and tetrahydrofuran (THF, 10.0 mL). The reaction mixture was cooled to 0 °C, and triethylamine (EtsN, 1.82 g, 2.51 mL, 3.2 equiv, 18.0 mmol) was added slowly. An exotherm was observed and controlled by the addition rate. After addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature overnight (16 hours). The reaction mixture became brown, and a white solid formed during the reaction (triethylamine hydrochloride (LbN’HCI) salt). The mixture was filtered to remove the Et?N*HCI salt. The resultant dark brown solution was used in the next step as is (telescope reaction). ’H NVIR spectroscopy indicated >90% purity with 0.079 equiv of EtsN’HCl salt. Assumed yield of A-(cyanomethyl)nicotinamide (905 mg, 5.1 mmol, 90%, 90% Purity): 'H NMR (500 MHz, CDCh) 8 9.07 (d, J= 2.3 Hz, 1H), 8.73 (dd, J= 4.8, 1.6 Hz, 1H), 8.23 (dt, J= 8.0, 2.0 Hz, 1H), 8.15 (t, J= 5.8 Hz, 1H), 7.44 (dd, J= 8.0, 4.9 Hz, 1H), 4.40 (d, J = 5.6 Hz, 2H); ESIMS m / z 162 ([M+H]+).EXAMPLE 2

[0041] Preparation of A-(cyanomethyl)nicotinamide (S2) from nicotinic acid

[0042] In a 500 mL round bottom flask equipped with mechanical stirrer, temperature probe and nitrogen inlet, 2-aminoacetonitrile hydrochloride (10.26 g, 1.05 equiv, 110.9 mmol) was stirred in THF (105.6 mL). Triethylamine (21.90 g, 30.2 mL, 2.05 equiv, 216.5 mmol) was added212574-US-PRV-l8 in one portion. The reaction mixture was heated to 30 °C. After stirring overnight, the mixture was used as is in the next step.

[0043] In a 500 mL round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet and vent tube, nicotinic acid (13.00 g, 1 equiv, 105.6 mmol) was stirred in THF (105.6 mL) at 20 °C. Piperidine-l-carbaldehyde (59.75 mg, 0.005 equiv, 528.0 micromoles (pmol)) was added. Oxalyl dichloride (13.40 g, 1 equiv, 105.6 mmol) was added via syringe over 10 minutes. The temperature was controlled to < 20 °C using a water bath. After 1 hour, triethylamine (10.69 g, 14.7 mL, 1 equiv, 105.6 mmol) was added dropwise (slight exotherm). The reaction mixture was stirred for 1 hour.

[0044] The 2-aminoacetonitrile mixture was cooled in an ice bath to 0 °C. To this was added the acid chloride suspension via syringe in small portions (over 1 hour). After addition was complete, the mixture was stirred while the cold bath was allowed to warm. After 20 hours, the suspension was fdtered. The filtrate was stored at room temperature.1H NMR spectroscopy indicated >90% purity.EXAMPLE 3

[0045] Preparation of A-(cyanomethyl)nicotinamide (S2) from nicotinic acid

[0046] In a 500 mL three-neck round bottom flask equipped with a half-moon impeller, temperature probe, and nitrogen inlet, nicotinic acid (13.00 g, 1.0 equiv, 105.6 mmol), and piperidine-l-carbaldehyde (59.75 mg, 0.0050 equiv, 0.5280 mmol) were stirred in dichloromethane (DCM, 105.6 mL) at 20 °C. Oxalyl dichloride (14.07 g, 1.050 equiv, 110.9 mmol) was added dropwise via syringe. The temperature was controlled below 20 °C using a water bath. After 3 hours, the reaction mixture was cooled to -10 °C in an ice / acetone bath. 2- Aminoacetonitrile hydrochloride (9.771 g, 1.000 equiv, 105.6 mmol) and DCM (105.6 mL) were added. Triethylamine (32.07 g, 3.000 equiv, 316.8 mmol) was added dropwise while keeping the212574-US-PRV-l temperature below 10 °C. After addition was complete, the mixture was stirred overnight allowing the ice / acetone bath to expire. After 20 hours, the reaction mixture was filtered to afford the solution of S2 in DCM. The DCM solution was concentrated. THF (60 mL) was added to the flask, and the resulting mixture was filtered again. The filtrate was concentrated to obtain tan-colored product which was used as is for subsequent steps.EXAMPLE 4

[0047] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S2)

[0048] In a stoppered four-neck 2-L round bottom flask equipped with a mechanical stirrer and a baffle, a mixture of 2-aminoacetonitrile hydrochloride (41.34 g, 1.1 equiv, 446.8 mmol) and DCM (507.7 mL) was stirred at room temperature. A-Methylmorpholine (90.38 g, 98.2 mL, 2.2 equiv, 893.5 mmol) was added in one portion. The mixture was stirred at room temperature overnight and then was used as is.

[0049] In a 1-L round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet, and vent tube, nicotinic acid (50.00 g, 1 equiv, 406.1 mmol) was stirred in DCM (507.7 mL) at 20 °C. Piperidine- 1-carbaldehy de (459.6 mg, 0.01 equiv, 4.061 mmol) was added. Oxalyl dichloride (51.55 g, 34.8 mL, 1 equiv, 406.1 mmol) was added via syringe over 30 minutes. The reaction mixture was stirred at room temperature overnight. A-Methylmorpholine (41.08 g, 44.7 mL, 1 equiv, 406.1 mmol) was added dropwise via syringe, and the mixture was used as is.

[0050] The 2-aminoacetonitrile mixture was cooled in an ice bath to < 5 °C. To this was added the acid chloride suspension via syringe in small portions (over 30 minutes). After addition was complete, the cold bath was removed. After 2 hours, the mixture was filtered, and the filtrate was concentrated. The concentrated filtrate was slurried in acetone and filtered. The filtrate so obtained was concentrated to 200 mL, which was loaded onto a silica cartridge (250212574-US-PRV-l10 g). Silica gel chromatography (220 g) with acetone as eluent provided an oil that was seeded affording the desired product S2 as a solid (66.44 g, 96% yield).EXAMPLE 5

[0051] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3)S2 S3

[0052] To a 25 mL vial were added sequentially / V-(cyanomethyl (nicotinamide (S2, 200 mg, 1 equiv, 1.24 mmol), THF (2.00 mL), and hydrogen sulfide (63.4 mg, 2.33 mL, 0.80 molar (M) in THF, 1.5 equiv, 1.86 mmol). Ethylamine (168 mg, 1.86 mL, 2 M in THF, 3 equiv, 3.72 mmol) was added slowly. The reaction mixture was stirred overnight at 40 °C.1H NMR spectroscopy suggested a clean conversion to A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 277 mg, 1.2 mmol, 95%, 95% Purity): 'H NMR (500 MHz, CDCh) 8 9.11 (dd, J= 22, 0.9 Hz, 1H), 8.78 (dd, .7 = 4.8, 1.7 Hz, 1H), 8.62 (s, 1H), 8.16 (dt, J= 8.1, 2.0 Hz, 1H), 7.82 (s, 1H), 7.43 (ddd, J= 7.9, 4.9, 1.0 Hz, 1H), 4.45 (d, J= 5.1 Hz, 2H), 3.74 (qd, J= 7.1, 4.9 Hz, 2H), 1.32 (t, J= 7.3 Hz, 3H); ESIMS m / z 224 ([M+H]+).EXAMPLE 6

[0053] Preparation of A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3)S2 S3

[0054] To a 500 mL jacketed glass reactor equipped with mechanical stirrer, vent gas scrubber, temperature probe, and nitrogen inlet, ethylamine (7.06 g, 78.3 mL, 2 M in THF, 2.5 equiv, 157 mmol) was added. The reactor jacket was set at 5 °C. Hydrogen sulfide (2.56 g, 93.9 mL, 0.8 M in THF, 1.2 equiv, 75.1 mmol) was then charged to the reactor in a controlled manner212574-US-PRV-l11 to form ethylamine-hydrogen sulfide salt solution. ,¥-(Cyanomethyl)nicotinamide (12 g, 1 equiv, 62.6 mmol, 84% purity) and THF (125 mL) were charged to the reactor, and the reaction contents were stirred at 40 °C for 8 hours. Following reaction completion, the contents of the reactor were sparged with nitrogen at 60 °C for 30 minutes. The product, A-(2-(ethylamino)-2- thioxoethyl)nicotinamide (S3), was collected as a 25.2 wt% (11.35 g, 81.2% yield) solution in THF.EXAMPLE 7

[0055] Preparation of A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3)

[0056] In a 500 mL round bottom flask equipped with mechanical stirrer, temperature probe, and nitrogen inlet, 2-aminoacetonitrile hydrochloride (9.77 g, 1 equiv, 106 mmol) was stirred in THF (106 mL). Triethylamine (21.4 g, 29.4 mL, 2 equiv, 211 mmol) was added in one portion. After stirring for 24 hours, the mixture was used as is in the next step.

[0057] In a 500 mL round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet, and vent tube, nicotinic acid (13.0 g, 1 equiv, 106 mmol) was stirred in THF (106 mL) at 20 °C. Piperidine- 1-carbaldehy de (59.7 mg, 0.005 equiv, 528 pmol) was added. Oxalyl dichloride (13.4 g, 9.06 mL, 1 equiv, 106 mmol) was added dropwise. The temperature was controlled to < 20 °C using a water bath. After 1 hour, triethylamine (10.7 g, 14.7 mL, 1 equiv, 106 mmol) was added dropwise (exotherm).

[0058] The 2-aminoacetonitrile mixture was cooled in an acetone cold bath to 0 °C. To this was added the acid chloride suspension via syringe in small portions (over 1 hour). After the212574-US-PRV-l addition was complete, the mixture was stirred while the cold bath was allowed to warm. After 20 hours, the suspension was filtered, and the filter cake was washed with THF until the eluent was colorless. The filtrate was diluted with methanol (MeOH, 200 mL) and transferred to a 1- liter (L) flask fitted with a mechanical stirrer and a vent gas scrubber. Ethanamine hydrochloride (EtNEb’HCl, 25.8 g, 3 equiv, 317 mmol) was added followed immediately by sodium sulfide (12.4 g, 1.5 equiv, 158 mmol). The stirred mixture was heated to 40 °C. After 24 hours, the mixture was filtered, concentrated, and diluted with THF to provide S3 as a THF solution.EXAMPLE 8

[0059] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)

[0060] In a 40 mL vial were added A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 500 mg, 98 wt%, 1 equiv, 2.19 mmol) and toluene (PhCH.i, 5.00 mL). A white slurry resulted. The slurry was heated to 50-70 °C for 30 minutes to improve solubility. A heterogeneous mixture remained. To this mixture was added concentrated sulfuric acid (1.08 g, 585 pL, 5 equiv, 11.0 mmol) dropwise. The reaction mixture was stirred at 50 °C for 90 minutes. A clear, colorless organic layer and a thick orange oil on the bottom of the vial remained. LC-MS analysis of the oil showed complete conversion of S3 to S4.

[0061] The reaction mixture was diluted dropwise with water (5 mL). The resulting two- phase mixture was treated dropwise with 10 normal (N) potassium hydroxide (KOH) solution until pH=8 and a cloudy aqueous layer resulted. This mixture was warmed to 70 °C, at which point all the solid dissolved, and the layers were separated. The organic layer was diluted with ethyl acetate (EtOAc, 20 mL) and washed with water (5 mL). The organic layer was dried over sodium sulfate (Na2SO4), filtered, and concentrated on a rotary evaporator to provide the desired product (0.401 g, -89% yield) as a tan powder: 'H NMR (500 MHz, CDCI3) 8 8.99 (d, J= 2.3 Hz, 1H), 8.54 (dd, J= 4.9, 1.6 Hz, 1H), 8.08 (dt, J = 8.0, 2.0 Hz, 1H), 7.32 (ddd, J= 8.1, 4.9, 0.9 Hz, 1H), 6.99 (s, 1H), 4.03 (s, 1H), 3.25 (q, J= 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H);13C NMR212574-US-PRV-l13(126 MHz, CDCI3) 5 152.04, 149.18, 149.13, 146.55, 132.20, 130.47, 123.62, 121.81, 43.06, 14.77.EXAMPLE 9

[0062] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of methanesulfonic acid

[0063] A 40 mL vial under nitrogen and equipped with a magnetic stir bar was charged with A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (500 mg, 2.24 mmol) and toluene (10.00 mL). The resulting suspension was warmed to 60 °C and treated dropwise with methanesulfonic acid (MsOH, 2.15 g, 1.45 mL, 22.4 mmol). The resulting mixture was stirred for 5 hours at 60 °C and cooled to 25 °C. Water (10 mL) was added, and the mixture was stirred for 5 minutes. The aqueous layer was separated to provide A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of methanesulfonic acid as a 2.04 wt% aqueous solution (16.27 g, 71.99% yield).EXAMPLE 10

[0064] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of benzenesulfonic acid

[0065] An 8 mL vial under nitrogen and equipped with a magnetic stir bar was charged with 7V-(2-(ethylamino)-2-thioxoethyl)nicotinamide (500 mg, 98 wt%, 2.19 mmol) and toluene (5 mL). The resulting suspension was treated dropwise with benzenesulfonic acid (1.21 g, 7.68 mmol) over 10 minutes. The resulting mixture was stirred for 4 hours at 80 °C and cooled to 25 °C. Water (3 mL) was added. An oily bottom layer was separated to provide A-ethyl-2-(pyridin- 3-yl)thiazol-5-amine salt of benzenesulfonic acid as a 7.35 wt% solution in water (4.29 g, 70.14% yield).EXAMPLE 11

[0066] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of trifluoromethanesulfonic acid

[0067] A 40 mL vial under nitrogen and equipped with a magnetic stir bar was charged with Ar-(2-(ethylamino)-2-thioxoethyl)nicotinamide (500 mg, 2.24 mmol) and dichloromethane (DCM, 10.00 mL). The resulting suspension was treated dropwise with trifluoromethanesulfonic212574-US-PRV-l14 acid (3.36 g, 1.98 mL, 22.4 mmol) at 25 °C over 10 minutes. The resulting mixture was stirred for 4 hours at 30 °C and cooled to 25 °C. Water (20 mL) was added. The aqueous layer was separated to provide 2V-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of trifluoromethanesulfonic acid as a 1.58 wt% solution in water (26.04 g, 89.24% yield).EXAMPLE 12

[0068] Preparation of V-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of sulfuric acid

[0069] An 8 mL vial under nitrogen and equipped with a magnetic stir bar was charged with JV-(2-(ethylamino)-2-thioxoethyl)nicotinamide (500 mg, 98 wt%, 2.19 mmol) and toluene (5.00 mL). The temperature was increased to 50 °C. Sulfuric acid (1.08 g, 585 pL, 11.0 mmol) was added dropwise over 10 minutes, and the reaction mixture was stirred for 3 hours. The mixture was then cooled to 25 °C, and the toluene layer was separated to provide A-ethyl-2-(pyridin-3- yl)thiazol-5-amine salt of sulfuric acid as a 20.96 wt% solution (1.87 g, 87.24% yield).EXAMPLE 13

[0070] Preparation of / V-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of hydrochloric acid

[0071] A 40 mL vial under nitrogen and equipped with a magnetic stir bar was charged with W-(2-(ethylamino)-2-thioxoethyl)nicotinamide (0.50 g, 2.2 mmol) and benzonitrile (5.00 mL). The mixture was heated to 80 °C, and phosphorus trichloride (0.78 g, 0.50 mL, 5.7 mmol) was added dropwise over 5 minutes. The mixture was stirred for 4 hours. The mixture was cooled to 25 °C to provide A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of hydrochloric acid as a 3.69 wt% solution in benzonitrile (6.14 g, 50.4% yield).EXAMPLE 14

[0072] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of hydrochloric acid

[0073] A 40 mL vial under nitrogen and equipped with a magnetic stir bar was charged with W-(2-(ethylamino)-2-thioxoethyl)nicotinamide (0.50 g, 2.2 mmol) and acetonitrile (7.00 mL). The temperature was increased to 80 °C, and phosphorus trichloride (1.54 g, 1.0 mL, 11.4 mmol) was added dropwise over 10 minutes. The resulting slurry was stirred at 80 °C for 6 hours. The212574-US-PRV-l15 mixture was cooled to 25 °C, and the product was filtered and washed with ethyl acetate (EtOAc). The filter cake was then dried to provide V-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of hydrochloric acid as a yellow powder (0.831 g, 52.34% yield).EXAMPLE 15

[0074] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of phosphoric acid

[0075] A 20 mL vial under nitrogen and equipped with a magnetic stir bar was charged with A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (500 mg, 2.24 mmol), toluene (5.00 mL) and polyphosphoric acid (2.19 g, 22.4 mmol) at 25 °C. The temperature was increased to 110 °C, and the reaction mixture was stirred for 3 hours. The mixture was cooled to 25 °C, and water (20 mL) was added. The aqueous layer was separated to provide A-ethyl-2-(pyridin-3-yl)thiazol-5-amine salt of phosphoric acid as a 1.16 wt% solution in water (21.78 g, 54.83% yield).EXAMPLE 16

[0076] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)S3 S4

[0077] Into a 500 mL round bottom flask were added 2-aminoacetonitrile hydrochloride (4.00 g, 1 equiv, 43.2 mmol), nicotinoyl chloride hydrochloride (8.08 g, 1.05 equiv, 45.4 mmol) and THF (200 mL). The resulting suspension was stirred vigorously as triethylamine (11.5 g, 15.8 mL, 3.05 equiv, 132 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was filtered to remove212574-US-PRV-l16E N-HCI and was concentrated to provide S2 as a brown oil which was used as is in the next reaction.

[0078] Into a 500 mL round bottom flask were added A-(cyanomethyl)ni cotinamide (S2, 6.97 g, 1 equiv, 43.2 mmol), ethanamine hydrochloride (10.6 g, 3 equiv, 130 mmol) and sodium sulfide (5.06 g, 1.5 equiv, 64.9 mmol). The resulting solids were treated with MeOH (150 mL) and the resulting heterogeneous mixture was warmed to 40 °C with vigorous stirring. After 20 hours, the reaction mixture was filtered through Celite®, and the Celite® pad was rinsed with MeOH (50 mL). The resulting solution was concentrated to a yellow oil by rotary evaporation. Toluene (50 mL) was added, and the resulting mixture was concentrated to a tan semisolid. More toluene (50 mL) was added, and the resulting slurry was again concentrated to a tan semisolid. This material was dried under vacuum overnight to afford S3 as a tan / brown powder (10.98 g).

[0079] Into a 500 mL round bottom flask were added A-(2-(ethylamino)-2- thioxoethyl)nicotinamide (S3, 9.66 g, 1 equiv, 43.26 mmol) and toluene (60.00 mL), resulting in an off-white slurry. The slurry was heated to 60 °C for 30 minutes, and to this mixture was added sulfuric acid (16.97 g, 9.22 mL, 4.0 equiv, 173.0 mmol) dropwise over 15 minutes. The mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to 25 °C and diluted slowly with water (50 mL) while maintaining the internal temperature <25 °C. The resulting mixture was diluted with EtOAc (30 mL). The aqueous layer was separated and was neutralized with 10 N KOH added dropwise to maintain the temperature <36 °C, resulting in a tan solid. The mixture was filtered, and the solid was dried under vacuum to provide A-ethyl-2-(pyri din-3 -yl)thiazol-5- amine (S4, 8.93 g, 48.3% over 3 telescoped steps) as a tan solid.EXAMPLE 17

[0080] Preparation of A-(cyanomethyl)nicotinamide hydrochloride (S2-HC1) from nicotinic212574-US-PRV-l17

[0081] To a 25 mL vial was added nicotinic acid (1.23 g, 1 equiv, 10.0 mmol), N,N- diisopropylethylamine (1.42 g, 1.1 equiv, 11.0 mmol) and DCM (20.0 mL). The solution was cooled to 5 °C (ice bath), and thionyl chloride (1.43 g, 1.2 equiv, 12.0 mmol) was added dropwise slowly. The resulting mixture was stirred for 2-3 hours at room temperature. After the reaction was complete by HPLC, the solution was concentrated under vacuum to half of the volume. A solution of 2-aminoacetonitrile hydrochloride (1.02 g, 1.1 equiv, 11.0 mmol) and A,A-diisopropylethylamine (1.42 g, 1.1 equiv, 11.0 mmol) in DCM (5.00 mL) was added. After completion of the reaction by HPLC, the slurry mixture was filtered and washed with DCM (5 mL) to collect the product A-(cyanomethyl)nicotinamide hydrochloride (1.90 g, 9.61 mmol, 96.1%) as a light-yellow solid after air-drying. Analytical data were consistent with structure.EXAMPLE 18

[0082] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N-(cyanomethyl)nicotinamide (S2)S2 S3

[0083] To a 25 mL vial were added hydrogen sulfide in THF (426 mg, 15.6 mL, 0.80 molar, 1.25 equiv, 12.5 mmol) and ethanamine in THF (564 mg, 6.25 mL, 2.00 molar, 1.25 equiv, 12.5 mmol), and the mixture was stirred for 0.5 hours at room temperature. To the suspension was added S2 (1.61 g, 1 equiv, 10.0 mmol), and the mixture was kept at 40 °C overnight. After completion of the reaction by HPLC, the reaction solvent was concentrated and replaced with water. The product, A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.81 g, 8.11 mmol, 81.1%), was isolated as an off-white solid. Analytical data were consistent with structure.EXAMPLE 19

[0084] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N-(cyanomethyl)ni cotinamide (S2)212574-US-PRV-l18S2 S3

[0085] To a 25 mL vial were added sodium hydrosulfide hydrate (NaSH«xH2O, 1.27 g, 55 wt%, 1.25 equiv, 12.5 mmol) and ethanamine hydrochloride (2.04 g, 2.5 equiv, 25.0 mmol) in water (5.00 mL), and the mixture was stirred for 0.5 hours at room temperature. To the suspension was added a solution of S2 (1.61 g, 1 equiv, 10.0 mmol) in water (5.00 mL), and the mixture was kept at 40 °C overnight. After completion of the reaction by HPLC, the product, N- (2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.71 g, 7.66 mmol, 76.6%), was isolated as an off-white solid. Analytical data were consistent with reference.EXAMPLE 20

[0086] Preparation of V-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N- (cyanomethyl)nicotinamide (S2)S2 S3

[0087] To a 25 mL vial were added sodium sulfide nonahydrate (Na2S*9H2O, 3.00 g, 1.25 equiv, 12.5 mmol) and ethanamine hydrochloride (2.04 g, 2.5 equiv, 25.0 mmol) in MeOH (5.00 mL), and the mixture was stirred for 0.5 hours at room temperature. To the suspension was added a solution of S2 (1.61 g, 1 equiv, 10.0 mmol) in MeOH (5.00 mL), and the reaction mixture was kept at 40 °C overnight. After completion of the reaction by HPLC, the solvent was replaced with water to isolate the product, A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.69 g, 7.57 mmol, 75.7%), as an off-white solid. Analytical data were consistent with reference.212574-US-PRV-l19EXAMPLE 21

[0088] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N-(cyanomethyl)ni cotinamide (S2) via isolation of the primary thioamideS2 | — primary thioamide, R = HL— S3, R = CH2CH3

[0089] Step 1 : To a 20 mL vial, A-(cyanomethyl)nicotinamide (S2, 1.5 g, 1 equiv, 9.31 mmol) and ammonium sulfide (1.65 g, 1.3 equiv, 12.1 mmol, 50 wt% aqueous solution) were added. Methanol (9 mL) was added to solubilize all the solids. The reaction mixture was stirred at 40 °C for 16 hours. The product precipitated out of the solution. The slurry was filtered, and the solids were dried to obtain the primary thioamide, A-(2-amino-2-thioxoethyl)nicotinamide (1.58 g, 86.9%): 'H NMR (400 MHz, DMSO4) 89.74 (s, 1H), 9.21 (s, 1H), 9.11 - 9.00 (m, 2H), 8.71 (dd, .7= 4.7, 1.9 Hz, 1H), 8.23 (dd, J= 8.0, 2.3 Hz, 1H), 7.52 (dd, J= 8.1, 4.7 Hz, 1H), 4.19 (d, J= 5.8 Hz, 2H);13C NMR (101 MHz, DMSO-r / e) 8 203.58, 165.61, 152.38, 149.20, 135.71, 130.07, 123.80, 50.08.

[0090] Step 2: To a 20 mL vial, ethanamine (83.1 mg, 0.92 mL, 2.00 molar in THF, 1.2 equiv, 1.84 mmol) was added. The vial temperature was set at 5 °C. Hydrogen sulfide (62.8 mg, 2.36 mL, 0.80 molar in THF, 1.2 equiv, 1.84 mmol) was added to the vial in a controlled manner to form ethanamine-hydrogen sulfide salt solution. A-(2-Amino-2-thioxoethyl)nicotinamide (300 mg, 1.54 mmol) and methanol (1 mL) were added to form a homogeneous solution. The reaction mixture was stirred at 40 °C for 16 hours. Analysis by ultra-performance liquid chromatography-mass spectroscopy (UPLC-MS) show 100% conversion to the product, N-(2- (ethylamino)-2-thioxoethyl)nicotinamide (S3) as a 10 wt% solution in THF / methanol. Analytical data were consistent with reference.212574-US-PRV-l20EXAMPLE 22

[0091] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N-(cyanomethyl)ni cotinamide hydrochloride (S2-HC1)S2-HCI S3

[0092] To a 25 mL vial were added sodium hydrogen sulfide hydrate (NaSH’xPLO, 712 mg, 55 wt%, 1.5 equiv, 6.98 mmol) and ethanamine hydrochloride (569 mg, 1.5 equiv, 6.98 mmol) in water (5.00 mL), and the mixture was stirred for 0.5 hours at room temperature. To the solution was added a solution of A-(cyanomethyl)nicotinamide hydrochloride (S2-HC1, 920 mg, 1 equiv, 4.66 mmol) in water (5.00 mL), and the reaction mixture was kept at 35-40 °C overnight. After completion of the reaction by HPLC, the reaction mixture was cooled to 0-5 °C (ice bath) for 0.5 hours. The product, ,V-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3, 0.94 g, 4.2 mmol, 90%) was isolated by filtration as an off-white solid. Analytical data were consistent with reference.EXAMPLE 23

[0093] Preparation of A-(2-ethylamino)-2-thioxoethyl)nicotinamide (S3) from N- (cyanomethyl)nicotinamide hydrochloride (S2-HC1)S2-HCI S3

[0094] To a 25 mL vial were added sodium sulfide nonahydrate (Na2S»9H2O, (1.68 g, 1.5 equiv, 6.98 mmol) and ethanamine hydrochloride (569 mg, 1.5 equiv, 6.98 mmol) in water (5.00 mL), and the mixture was stirred for 0.5 hours at room temperature. To the solution was added a solution of S2 (920 mg, 1 equiv, 4.66 mmol) in water (5.00 mL), and the reaction mixture was kept at 35-40 °C overnight. After completion of the reaction by HPLC, the reaction mixture was cooled to 0-5 °C (ice bath) for 0.5 hours. The product, A-(2-(ethylamino)-2-212574-US-PRV-l21 thioxoethyl)nicotinamide (S3, 0.60 g, 2.7 mmol, 58%), was isolated by filtration as an off-white solid. Analytical data were consistent with reference.EXAMPLE 24

[0095] General Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)

[0096] To methanesulfonic acid (MsOH, 14.40 g, 15.0 mmol, 15 equiv) in a 100-mL three- neck round bottom flask equipped with a condenser, a thermocouple, a magnetic stirrer, and a nitrogen blanket was added A-(2-(ethylamino)-2-thioxoethyl )nicotinamide (S3, 2.23 g, 10 mmol) at 20 °C. An exothermic reaction occurred where the temperature increased from 20 °C to 33 °C over 10 minutes, forming a light brown solution. The reaction mixture was heated to 60 °C over 15 minutes and was kept stirring at 60 °C until the reaction was complete (in 2 to 4 hours as monitored by 'H NMR spectroscopy or UPLC). The resulting mixture was allowed to cool to ambient temperature (20 °C) and diluted with deionized water (40 mL). After cooling to 0-5 °C, 50 wt% NaOH was added dropwise to adjust the pH to 9-10. The desired product, S4, precipitated, was collected by filtration with rinsing with deionized water (5 mL), and was dried in a vacuum oven at 50 °C and 1-10 mmHg overnight. Yields ranged from 1.77 g to 1.91 g (86- 93%). Analytical data were consistent with reference.EXAMPLE 25

[0097] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)

[0098] V-(2-(Ethylamino)-2-thioxoethyl)nicotinamide (S3, 4.46 g, 20 mmol) was added to methanesulfonic acid (MsOH, 28.83 g, 300 mmol, 15 equiv) at 20 °C in a 50-mL three-neck212574-US-PRV-l round bottom flask equipped with a condenser, a thermocouple, a magnetic stirrer, and a nitrogen blanket. An exothermic reaction occurred where the temperature increased from 20 °C to 42 °C in 10 minutes, forming a light brown solution. The reaction mixture was heated to 60 °C in 5 minutes and was kept stirring at 60 °C until the reaction was complete 'H NMR spectroscopy or UPLC (4 hours). The reaction mixture was allowed to cool to ambient temperature (20 °C). A total of 33.25 g of the reaction mass was collected. (~ 50 mg was used during sampling.)

[0099] Isolation of S4 without recovery of MSA: A sample of 6.23 g of the above reaction mass (18.71% of the total) was diluted with deionized water (15 mb) and cooled to 0-5 °C with ice water. 50 wt% NaOH was added dropwise to adjust the pH to 10-12. (4.6 g of 50% NaOH was consumed.) The desired product, S4, precipitated, was filtered and rinsed with deionized water (2 x 5 mL), was suction dried, and further dried in a vacuum oven at 45-50 °C and 1-10 mmHg (0.71 g, 93% yield on mass).

[0100] Isolation of S4 with recovery of MSA: A sample of 3.31 g of the above reaction mass (10% of the total) was mixed with isobutyl acetate (z-BuOH, 8.80 g) for 30 minutes and was allowed to settle for phase separation. After 30 minutes, the phases (z-BuOH and oil) were separated. The oil phase (bottom) was extracted with z-BuOH (2x, 8.75 g and 4.66 g, respectively). The remaining thick oil was dissolved in deionized water (10 mL). 50% NaOH was added to adjust the pH to 10-12. (0.80 g of 50% NaOH was used.) The precipitated solid was filtered, rinsed with deionized water (5 mL), and dried (0.35 g, 86% yield on mass). The z- BuOH phases were combined and concentrated to dryness by rotary evaporation (9-10 mmHg at 40-60 °C) to give MSA residue (2.52 g, 88% recovery on mass, containing a small amount of S4).EXAMPLE 26

[0101] Preparation of 2V-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)212574-US-PRV-l

[0102] Ar-(2-(Ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.00 g, 1 equiv, 4.48 mmol) and 1,4-dioxane (10.0 mL) were added to a round bottom flask. The resulting suspension was warmed to 60 °C to give a colorless, mostly homogeneous mixture. The reaction mixture was treated with fuming sulfuric acid (1.76 g, 955 pL, 4 equiv, 17.9 mmol) dropwise over 10 minutes. A sticky oil initially formed but with vigorous stirring a tan suspension formed. Upon reaction completion as determined by UPLC / MS (~2 hours), the suspension was cooled to ambient temperature to provide a tan slurry. The slurry was filtered and washed with dioxane. The solid was dried under vacuum at 50 °C providing a yellow powder (1.698 g, 93%). Ion chromatography confirmed a 2:1 ratio of sulfate to free base (S4)

[0103] The free base, S4, was prepared by the product from above (0.5 g) in water (3 mL) to provide an orange solution. The solution was adjusted with 47% KOH solution (aqueous) to pH=10. A tan solid formed. The aqueous suspension was filtered, and the solid filter cake was dried under vacuum (0.25 g, 97%) as a tan powder. Analytical data were consistent with structure.EXAMPLE 27

[0104] Preparation of A-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S4)

[0105] A-(2-(Ethylamino)-2-thioxoethyl)nicotinamide (S3, 1.00 g, 1 equiv, 4.48 mmol) and trichloroacetic acid (6.00 mL) were added to a round bottom flask with magnetic stirring. (Note: Trichloroacetic acid was a solid at ambient temperature). The resulting mixture was warmed slowly to 80 °C and the mixture became homogeneous. The resulting solution was then treated dropwise with fuming sulfuric acid (1.32 g, 716 pL, 3 equiv, 13.4 mmol) over 10 minutes to provide a yellow / orange solution. (A slight exotherm resulted.) The reaction was determined to be complete after being stirred for 1 hour at 80 °C. The reaction mixture was cooled to ambient temperature and stored overnight, during which time the mixture solidified and a tan solid was obtained. The reaction mixture was dissolved in water (20 mL) and the resulting solution was212574-US-PRV-l24 adjusted to pH=10 with 2 N KOH. The resulting suspension was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dried under vacuum to provide a tan solid (0.905 g, 3.9 mmol, 87%, 88% Purity), whose analytical data were consistent with / V-ethyl-2- (pyridin-3-yl)thiazol-5-amine (S4), with a trace amount of unreacted S3 and minor impurities.

[0106] Consequently, in light of the above the following additional, non-exhaustive, details (D) are provided.ID. A molecule, A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3), having the following formula2D. A process for the preparation of a molecule according to ID the process comprising: reactingS2 or a salt thereof with a thiolation reagent and ethylamine or ethanamine hydrochloride in the presence of a solvent.3D. The process according to 2D, wherein the thiolation reagent is sodium hydrogen sulfide or hydrate thereof, sodium sulfide, ammonium sulfide, hydrogen sulfide, or pre-formed ethylamine-hydrogen sulfide salt.4D. The process according to 2D or 3D, wherein the amount of thiolation reagent is from about 1 mole to about 5 moles of thiolation reagent per mole of S2.5D. The process according to 2D or 3D, wherein the amount of thiolation reagent is from about 1.3 moles to about 3.5 moles of thiolation reagent per mole of S2.212574-US-PRV-l256D. The process according to any one of 2D-5D, wherein the amount of ethylamine or ethanamine hydrochloride is from about 1 mole to about 5 moles of ethylamine or ethanamine hydrochloride per mole of S2.7D. The process according to any one of 2D-5D, wherein the amount of ethylamine or ethanamine hydrochloride is from about 1.3 moles to about 3.5 moles of ethylamine or ethanamine hydrochloride per mole of S2.8D. The process according to any one of 2D-7D, wherein the solvent is dichloromethane (“DCM”), chlorobenzene (“PhCl”), tetrahydrofuran (“THF”), water, methanol (“MeOH”), ethanol (“EtOH”), isopropyl alcohol (z-PrOH), or mixtures thereof.9D. The process according to any one of 2D-8D, wherein the process is conducted at a temperature from about 0 °C to about 50 °C.10D. The process according to any one of 2D-8D, wherein the process is conducted at a temperature from about 10 °C to about 45 °C.1 ID. The process according to any one of 2D-10D, wherein the process is conducted at ambient pressure.12D. The process according to any one of 2D-11 D, wherein the product of the process (S3) i s isolated.13D. A process for the preparation of a molecule according to ID the process further comprising: reactinga. S1 , wherein X1is OH (Sla) or Cl (Sib) or a hydrochloride salt thereof (*HC1, Slb-HCl); and b. 2-aminoacetonitrile or 2-aminoacetonitrile hydrochloride in the presence of a base and a solvent to provide S2 or S2-HC1.14D. The process according to 13D, wherein the base is an organic base.212574-US-PRV-l2615D. The process according to 14D, wherein the organic base is pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, 5-ethyl-2-methylpyridine, A,A-diisopropylethylamine (“DIPEA”), N- methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, triethylamine (“EtsN”), or mixtures thereof.16D. The process according to 13D, wherein the base is an inorganic base.17D. The process according to 16D, wherein the inorganic base is potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (‘“NfeCCh”), sodium bicarbonate (“NaEICCh”), or mixtures thereof.18D. The process according to any one of 13D-17D, wherein an appropriate amount of base per mole of Sib is used to provide S2 or S2-HC1.19D. The process according to any one of 13D-17D, wherein an appropriate amount of base per mole of Slb-HCl is used to provide S2 or S2-HC1.20D. The process according to any one of 13D-19D, wherein the solvent is ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), di chloromethane ("DCM”), 1,2-di chloroethane, chlorobenzene (“PhCl”), 1,2-di chlorobenzene, toluene (“PhCEE”), or mixtures thereof.2 ID. The process according to any one of 13D-20D, wherein the process is conducted at a temperature from about -10 °C to about 25 °C.22D. The process according to any one of 13D-20D, wherein the process is conducted at a temperature from about 0 °C to about 20 °C.23D. The process according to any one of 13D-22D, wherein the process is conducted at ambient pressure.24D. The process according to any one of 13D-22D, wherein the product of the process (S2) is isolated.25D. The process according to 13D, wherein Sib is prepared in situ from Sla, in the presence of a carboxylic acid activator, a base, a solvent, and optionally a catalyst.26D. The process according to 25D, wherein the carboxylic acid activator is thionyl chloride, oxalyl chloride, and pivaloyl chloride.212574-US-PRV-l27D. The process according to 25D or 26D, wherein the amount of carboxylic acid activator is from about 0.9 moles to about 1.3 moles of carboxylic acid activator per mole of Sla.28D. The process according to 25D or 26D, wherein the amount of carboxylic acid activator is from about 1.0 moles to about 1.2 moles of carboxylic acid activator per mole of Sla.29D. The process according to any one of 25D-28D, wherein the base is an organic base.30D. The process according to 29D, wherein the organic base is selected from pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, 5-ethyl-2-methylpyridine, A,A-diisopropylethylamine (“DIPEA”), N- methylimidazole (“NMI”), A-methylmorpholine (“NMM”), tributylamine, triethylamine (“EtsN”), or mixtures thereof.3 ID. The process according to any one of 25D-28D, wherein the base is an inorganic base. 32D. The process according to 3 ID, wherein the inorganic base is potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaEICCh”), or mixtures thereof.33D. The process according to any one of 25D-32D, wherein the amount of base is from about 0.9 mole to about 1.3 moles of base per mole of Sla.34D. The process according to any one of 25D-32D, wherein the amount of base is from about 1.0 mole to about 1.2 moles of base per mole of Sla.35D. The process according to any one of 25D-34D, wherein the solvent is ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), di chloromethane ("DCM”), 1,2-di chloroethane, chlorobenzene (“PhCl”), 1,2-di chlorobenzene, toluene (“PhCEh”), or mixtures thereof.36D. The process according to any one of 25D-35D, wherein the optional catalyst is N,N- dimethylformamide (“DMF”) or piperidine- 1-carbaldehy de.37D. A process comprising converting the molecule of ID (S3) to S4 or salts thereof in the presence of a Lewis or Bronsted acid212574-US-PRV-l2838D. The process according to 37D, wherein the Lewis or Bronsted acid is sulfuric acid (“H2SO4”), fuming sulfuric acid (“H2SO4 + SO3”), phosphorus trichloride (“PCh”), phosphorus oxychloride (“POCI3”), polyphosphoric acid, methanesulfonic acid (“MsOH”), trifluoromethanesulfonic acid (“TfOH”), anhydrous / oluenesulfonic acid, or benzenesulfonic acid.39D. The process according to 37D or 38D, wherein the amount of Lewis or Bronsted acid is from about 1.5 moles to about 25 moles of Lewis or Bronsted acid per mole of S3.40D. The process according to 37D or 38D, wherein the amount of Lewis or Bronsted acid is from about 2.5 moles to about 15 moles of Lewis or Bronsted acid per mole of S3.41D. The process according to any one of 37D-40D, further comprising a solvent.42D. The process according to any one of 37D-41D, wherein the solvent is chlorobenzene (“PhCl”), sulfolane, dimethyl carbonate, 1,4-di oxane, propylene carbonate, acetonitrile (“ACN”), benzonitrile, 1,2-dichlorobenzene, dichloromethane ("DCM”), toluene (“PI1CH3”), trifluoroacetic acid (“TFA”), trichloroacetic acid (“TCA”), or mixtures thereof.43D. The process according to any one of 37D-42D, wherein the process is conducted at a temperature from about 20 °C to about 120 °C.44D. The process according to any one of 37D-42D, wherein the process is conducted at a temperature from about 25 °C to about 110 °C.45D. The process according to any one of 37D-44D, wherein the process is conducted at ambient pressure.46D. The process according to any one of 2D-45D, wherein the process is conducted in a telescope manner.

[0107] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0108] The use of the terms “a”, “an”, “the”, “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly212574-US-PRV-l29 contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0109] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

212574-US-PRV-l30WE CLAIM1. A molecule, A-(2-(ethylamino)-2-thioxoethyl)nicotinamide (S3), having the following formula2. A process for the preparation of the molecule according to claim 1 (S3), the process comprising: reactingor a salt thereof with a thiolation reagent and ethylamine or ethanamine hydrochloride in the presence of a solvent.

3. The process according to claim 2, wherein the thiolation reagent is sodium hydrogen sulfide or hydrate thereof, sodium sulfide, ammonium sulfide, hydrogen sulfide, or pre-formed ethylamine-hydrogen sulfide salt.

4. The process according to claim 2 or claim 3, wherein from about 1 mole to about 5 moles of the thiolation reagent per mole of S2 or from about 1.3 moles to about 3.5 moles of the thiolation reagent per mole of S2 is used.212574-US-PRV-l315. The process according to any one of claims 2-4, wherein from about 1 mole to about 5 moles of the ethylamine or ethanamine hydrochloride per mole of S2 or from about 1.3 moles to about 3.5 moles of the ethylamine or ethanamine hydrochloride per mole of S2 is used.

6. The process according to any one of claims 2-5, wherein the solvent is dichloromethane (“DCM”), chlorobenzene (“PhQ”), tetrahydrofuran (“THF”), water, methanol (“MeOH”), ethanol (“EtOH”), isopropyl alcohol (“z-PrOH”), or mixtures thereof.

7. The process according to any one of claims 2-6, wherein the reacting is conducted at temperatures from about 0 °C to about 50 °C or from about 10 °C to about 45 °C.

8. The process according to any one of claims 2-7, wherein the reacting is conducted at ambient pressure.

9. A process comprising converting the molecule of claim 1 (S3) to S4 or salts thereof in the presence of a Lewis or Bronsted acid10. The process according to claim 9, wherein the Lewis or Bronsted acid is sulfuric acid (“H2SO4”), fuming sulfuric acid (“H2SO4 + SO3”), phosphorus trichloride (“PCI3”), phosphorus oxychloride (“POCI3”), polyphosphoric acid, methanesulfonic acid (“MsOH”), trifluoromethanesulfonic acid (“TfOH”), anhydrous / z-toluenesulfonic acid, or benzenesulfonic acid.

11. The process according to claim 9 or claim 10, wherein from about 1.5 moles to about 25 moles of the Lewis or Bronsted acid per mole of S3 or from about 2.5 moles to about 15 moles of the Lewis or Bronsted acid per mole of S3 is used.212574-US-PRV-l3212. The process according to any one of claims 9-11, wherein the converting further comprises a solvent, wherein the solvent is chlorobenzene (“PhCl”), sulfolane, dimethyl carbonate, 1,4-di oxane, propylene carbonate, acetonitrile (“ACN”), benzonitrile, 1,2- di chlorobenzene, di chloromethane ("DCM”), 1,2-di chloroethane, toluene (“PI1CH3”), trifluoroacetic acid (“TFA”), trichloroacetic acid (“TCA”), or mixtures thereof.

13. The process according to any one of claims 9-12, wherein the converting is conducted at temperatures from about 20 °C to about 120 °C or from about 25 °C to about 110 °C.

14. The process according to any one of claims 9-13, wherein the converting is conducted at ambient pressure.

Images