One-step process to form n-ethyl-3-(methylsulfonyl)-n-(2-(pyridin-3-YL)thiazol-5-YL)propanamide

Abstract

Provided herein is a one-step process to prepare N-ethyl-3-(methylsulfonyl)-N-(2- (pyridin-3-yl)thiazol-5-yl)propanamide (S3)

Description

ONE-STEP PROCESS TO FORM N-ETHYL-3-(METHYLSULFONYL)-N-(2-(PYRIDIN-3- YL)THIAZOL-5-YL)PROPANAMIDE CROSS REFERENCE TO RELATED TO APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 680,289 filed August 7, 2024, which is expressly incorporated by reference herein. BACKGROUND

[0002] Preparation 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. SUMMARY

[0003] A molecule, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (also known as “S3” herein), having the following formula has been disclosed in PCT / US2024 / 014736.

[0004] Provided herein is a one-step process to prepare N-ethyl-3-(methylsulfonyl)-N-(2- (pyridin-3-yl)thiazol-5-yl)propanamide (S3) comprising: coupling N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1) or N-ethyl-2-(pyridin-3-yl)thiazol- 5-amine dihydrochloride (S1-HCl) with 3-(methylsulfonyl)propanoic acid (S2) in the presence of a carboxylic acid activator, a base, and a solvent. DETAILED DESCRIPTION

[0005] A molecule, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (also known as “S3” herein), having the following formula has been disclosed in PCT / US2024 / 014736. Molecule S3 has shown activity against green peach aphid (Myzus persicae, i.e., 71% control at 200 parts per million (ppm)).

[0006] One-step processesS3 may be useful in the process to prepare N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3- (methylsulfonyl)propanamide (also known as “S4” herein) and shown below.

[0007] Definitions

[0008] These definitions are only to be used for the purposes of this disclosure.

[0009] The term “ambient pressure” refers pressures from about 80 kilopascals (kPa) to about 105 kPa.

[0010] The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.

[0011] Scheme Oneyl)thiazol-5-amine (S1) or N-ethyl-2-(pyridin-3-yl)thiazol-5-amine dihydrochloride (S1-HCl) reacts with 3-(methylsulfonyl)propanoic acid (S2) in the presence of a carboxylic acid activator, a base, and a solvent to form S3. It has surprisingly been found that the reaction in Scheme One may be done in one step and one reactor (i.e., “one pot”) rather than in two steps and two reactors (i.e., first by forming an activated form of S2 which is then reacted with S1 or S1-HCl).

[0013] In one embodiment, the reaction in Scheme One is conducted with S1 that has been isolated from solution as the free base solid.

[0014] In one embodiment, the reaction in Scheme One is conducted with S1 that has been isolated from solution as the dihydrochloride salt (S1-HCl).

[0015] The reaction in Scheme One is conducted where, in general, from about 1 mole to about 1.175 moles of S2 per mole of S1 or S1-HCl may be used; more preferably, from about 1.05 moles to about 1.15 moles of S2 per mole of S1 or S1-HCl may be used.

[0016] The reaction in Scheme One is conducted in the presence of a carboxylic acid activator. Examples of carboxylic acid activators are pivalic anhydride and pivaloyl chloride. Ingeneral, from about 1 mole to about 1.5 moles carboxylic acid activator per mole of S1 or S1- HCl may be used; more preferably, from about 1.02 moles to about 1.2 moles of carboxylic acid activator per mole of S1 or S1-HCl may be used.

[0017] The reaction in Scheme One is conducted in the presence of a base. Examples of bases are pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, N,N-diisopropylethylamine (“DIPEA”), N-methylimidazole (“NMI”), and triethylamine (“Et3N”). In general, from about 1 mole to about 3 moles of base per mole of S1 may be used; more preferably, from about 1.1 moles to about 2.3 moles of base per mole of S1 may be used. In general, from about 1 mole to about 8 moles of base per mole of S1-HCl may be used; more preferably, from about 3.5 moles to about 7 moles of base per mole of S1-HCl may be used.

[0018] The reaction in Scheme One is conducted in the presence of a solvent. Examples of solvents are ethyl acetate (“EtOAc”), isobutyl acetate (“i-BuOAc”), tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), benzonitrile (“PhCN”), and toluene (“PhCH3”). Optionally, mixtures of such solvents may be used.

[0019] The reaction in Scheme One may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about 5 °C to about 50 °C may be used; preferably temperatures from about 10 °C to about 40 °C may be used.

[0020] In another embodiment, the reaction in Scheme One is conducted in one reaction vessel and utilizes fewer equivalents of S2 than in conventional methods.

[0021] In conventional methods, S3 may be prepared in a two-step procedure including activation of S2 followed by reaction with S1.

[0022] In another embodiment, the reaction in Scheme One may be conducted at a concentration of S1 or S1-HCl of from about 5 weight percent (wt%) to about 15 wt%.

[0023] In another embodiment, the reaction in Scheme One may be conducted at a concentration of S1 or S1-HCl of from about 5.0 weight percent (wt%) to about 10 wt%.

[0024] In another embodiment, the of the reaction in Scheme One, S3, is isolated from an isolation solvent.

[0025] In yet another embodiment, the product of the reaction in Scheme One, S3, is isolated from an isolation solvent. Examples of isolation solvents are polar protic solvents or polar aprotic solvents. Examples of polar protic solvents include water, aqueous hydrochloric acid, aqueous formic acid, methanol, ethanol, and propan-2-ol. Examples of polar aprotic solvents include ethyl acetate (“EtOAc”), isobutyl acetate (“i-BuOAc”), tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), and benzonitrile (“PhCN”).

[0026] In another embodiment, the product of the reaction in Scheme One, S3, is not isolated from the isolation solvent and may be used without further manipulation.

[0027] Examples provided herein are not exhaustive and should not be construed as limiting. COMPARATIVE EXAMPLE A

[0028] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)

[0029] 3-(Methylsulfonyl)propanoic acid (3.55 g, 1.2 equiv, 23.3 mmol) was charged into a 250-mL jacketed reactor with a bath temperature set to 25 °C. DCM (42.2 g, 497 mmol) and 3,5- dimethylpyridine (1.25 g, 0.60 equiv, 11.7 mmol) were added. The mixture was agitated. The bath temperature was increased to 35 °C. Pivaloyl chloride (3.11 g, 1.3 equiv, 25.8 mmol) was added. The solution was held at 35 °C for 2 hours after addition completion to allow conversion of the acid to the pivalic anhydride, 3-(methylsulfonyl)propanoic pivalic anhydride.

[0030] S1 was prepared in solution from HCl according to the procedure in Example 12 in PCT / US2022 / 074322. Dichloromethane was removed by distillation and the solids were dried under vacuum at 40 °C for 16 hours to afford S1 as a yellow solid (95%).

[0031] S1 (4.00 g, 1 equiv, 19.5 mmol) was charged into a 100 mL glass reactor at ambient conditions. DCM (42.2 g, 497 mmol) and 3,5-dimethylpyridine (3.22 g, 1.5 equiv, 30.0 mmol) were added, and the solution was agitated. The solution of S1 was transferred into the solution of 3-(methylsulfonyl)propanoic pivalic anhydride at 35 °C. The reaction mixture was stirred for 20 hours at 29-34 °C. Methanol (31.6 g, 989 mmol) was added to the mixture, and the mixture was concentrated by vacuum distillation to 20 mL. Methanol (31.6 g, 989 mmol) was added, and the mixture was concentrated by vacuum distillation to 20 mL. Methanol (15.8 g, 494 mmol) was added to the mixture at 50 °C. The slurry was cooled to 10 °C over 3 hours, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed two times with methanol (15.8 g, 494 mmol), and the solids were dried in a vacuum oven at 50 °C for 16 hours to afford N-ethyl-3- (methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S3 (5.74 g, 87% yield).1H NMR data obtained were consistent with S3. COMPARATIVE EXAMPLE B

[0032] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)

[0033] (methylsulfonyl)propanoic acid (22.26 grams (g), 1.2 equivalents (equiv), 146.3 millimoles (mmol)) and dichloromethane (DCM, 198 g, 150 milliliters (mL)) were charged. Pivaloyl chloride (20.58 g, 1.4 equiv, 170.7 mmol) was charged to the reactor using a peristaltic pump.3- Methylpyridine (14.76 g, 1.3 equiv, 158.5 mmol) was charged slowly to the reactor whilemaintaining the temperature between 10–15 The reaction mixture was stirred for 1 hour leading to the formation of the mixed anhydride.

[0034] In a secondary reactor, N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1 prepared according to Example 1, 25.51 g, 1 equiv, 121.9 mmol), DCM (258 g, 200 mL), and 3- methylpyridine (11.35 g, 1 equiv, 121.9 mmol) were charged to form a homogeneous solution. This solution was then slowly charged to the reactor containing mixed anhydride. Following the addition, the jacket temperature was increased to 35 °C, and the reaction mixture was stirred for 20 hours. The mixture was concentrated by vacuum distillation until the slurry volume reached about 200 mL. Methanol (200 g, 250 mL) was added to the mixture, and the mixture was concentrated by vacuum distillation. Additional methanol (200 g, 250 mL) was added, and the mixture was again concentrated by vacuum distillation. The slurry was cooled to 0–5 °C, maintained at 0–5 °C for 1 hour, and filtered. The wet cake was washed with additional methanol (50 g, 63 mL; x2), and the solids were dried in a vacuum oven at 50–55 °C overnight to afford N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3, 36 g, 106 mmol, 87%) as a light-yellow solid. EXAMPLE 1

[0035] Synthesis and Isolation of N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1)

[0036] In a 1-liter (L) jacketed reactor were added N-ethyl-2-(pyridine-3- carbothioamido)acetamide (A, 19.98 g, 1 equiv, 0.09 moles (mol)) and acetonitrile (ACN, 271 mL). A yellow slurry resulted. The slurry was heated to 25 °C and stirred at 500 revolutions per minute (rpm) for 15 minutes to improve solubility. A heterogeneous mixture remained. To this mixture was added anhydrous hydrochloric acid (1.2 g, 0.37 equiv, 0.03 mol) over 50 minutes. The solution was stirred for 40 minutes. To this mixture was added phosphorus trichloride (35.9g, 2.9 equiv, 0.26 mol) dropwise over 100 The reaction mixture was heated to 60 °C for 10 hours.

[0037] Acetonitrile was removed from the reaction mixture by distillation at 50 °C and ~20 kPa (150 torr). Toluene (PhCH3, 294 mL) was added as the acetonitrile was being removed. Distillation was discontinued when 1.4 wt% acetonitrile remained. The solution was cooled to 20 °C and water (61 mL) was added to the solution over 1 hour. To this biphasic mixture was added aqueous sodium hydroxide (7.48 g, 25 wt%, 0.5 equiv, 0.04 mol) dropwise. The temperature was increased to 50 °C over 30 minutes. The mixture was stirred at 50 °C for 15 minutes then agitation was stopped to allow for layer separation. The organic layer was removed. The dark red aqueous layer was cooled to 20 °C. To the aqueous layer was added aqueous sodium hydroxide (70.0 g, 10 wt%, 1.95 equiv, 0.17 mol) dropwise over 160 minutes. During the addition, a yellow-beige solid formed in solution. When the pH of the solution reached 10.6, the addition of aqueous sodium hydroxide was stopped, and the solution was stirred at 20 °C for one hour. The solution was filtered, and the pale-yellow solid was collected. The solid was washed twice with water (136 mL total). The solid was dried in a vacuum oven at 50 °C overnight. The product, N- ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1), was obtained as a pale-yellow powder and analyzed via quantitative high-performance liquid chromatography (12.86 g, 70% yield, 93.3 wt% purity):1H NMR (400 MHz, CDCl3): δ 8.98 (d, J = 2.3 Hz, 1H), 8.53 (dd, J = 4.8, 1.5 Hz, 1H), 8.07 (dt, J = 8.1, 2.0 Hz, 1H), 7.31 (dd, J = 8.0, 4.8 Hz, 1H), 6.98 (s, 1H), 3.79 (s, 1H), 3.24 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, CDCl3): δ 151.99, 149.13, 146.56, 132.23, 130.48, 123.61, 121.97, 77.21, 43.11, 14.78. EXAMPLE 2

[0038] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)2- (pyridin-3-yl)thiazol-5-amine (S1, 10.3 g, 1 equiv, 50.0 mmol), dichloromethane (172 g, 130 mL) and 3-methylpyridine (5.59 g, 1.2 equiv, 60.0 mmol) were charged into a 250-mL jacketed reactor with the bath temperature set to 15 °C. Pivaloyl chloride (6.63 g, 1.1 equiv, 55.0 mmol) was added slowly. The temperature increased to 36 °C. The reaction mixture was stirred for 20 hours at 35–37 °C. After completion of the reaction, methanol (79.5 g, 100 mL) was added to the mixture, and the mixture was concentrated by vacuum distillation. Additional methanol (79.5 g, 100 mL) was added, and the mixture was again concentrated by vacuum distillation. The slurry was cooled to 10–15 °C, maintained at 10–15 °C for 1 hour, and filtered. The wet cake was washed with additional cold methanol, and the solids were dried in a vacuum oven at 45–50 °C overnight to afford N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3, 15.0 g, 44.2 mmol, 88.4%) as a light-yellow solid. EXAMPLE 3

[0040] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3), (methylsulfonyl)propanoic acid (S2, 16.74 g, 1.1 equiv, 110.0 mmol), dichloromethane (264 g, 200 mL, 31.1 equiv, 3.11 mol) and 3-methylpyridine (20.49 g, 2.2 equiv, 220.0 mmol) werecharged into a 1-L jacketed reactor with the set to 15 °C. Pivaloyl chloride (13.87 g, 1.15 equiv, 115.0 mmol) was added slowly over 20 minutes. The temperature increased to 36 °C. The reaction mixture was stirred for 20 hours at 35–37 °C. After completion of the reaction by HPLC, methanol (158 g, 200 mL, 49.4 equiv, 4.94 mol) was added to the mixture, and the mixture was concentrated by vacuum distillation. Additional methanol (158 g, 200 mL, 49.4 equiv, 4.94 mol) was added, and the mixture was again concentrated by vacuum distillation. The slurry was cooled to 10 °C, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed with additional cold methanol (158 g, 200 mL, 49.4 equiv, 4.94 mol), and the solids were dried in a vacuum oven at 45–50 °C overnight to afford N-ethyl-3-(methylsulfonyl)-N-(2- (pyridin-3-yl)thiazol-5-yl)propanamide (S3, 30.9 g, 91.0 mmol, 91.0%) as a light-yellow solid. EXAMPLE 4

[0042] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)(methylsulfonyl)propanoic acid (S2, 7.99 g, 1.05 equiv, 52.5 mmol), dichloromethane (145 g, 110 mL, 34.2 equiv, 1.71 mol) and 3-methylpyridine (5.59 g, 1.2 equiv, 60.0 mmol) were charged into a 250 mL jacketed reactor with the bath temperature set to 15 °C. Pivaloyl chloride (6.63 g, 1.1 equiv, 55.0 mmol) was added slowly. The temperature increased to 36 °C. The reaction mixture was stirred for 20 hours at 35–37 °C. After completion of the reaction, propan- 2-ol (86.0 g, 110 mL, 28.6 equiv, 1.43 mol) was added to the mixture, and the mixture was concentrated by vacuum distillation. The slurry was cooled to 10 °C, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed with additional cold propan-2-ol (86.0 g, 110 mL, 28.6 equiv, 1.43 mol), and the solids were dried in a vacuum oven at 45–50 °C overnight toafford N-ethyl-3-(methylsulfonyl)-N-(2- 3-yl)thiazol-5-yl)propanamide (S3, 15.3 g, 45.1 mmol, 90.2%) as a light-yellow solid. EXAMPLE 5

[0044] Synthesis of and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)(methylsulfonyl)propanoic acid (S2, 16.74 g, 1.1 equiv, 110.0 mmol), dichloromethane (264 g, 200 mL, 31.1 equiv, 3.11 mol) and 3-methylpyridine (20.49 g, 2.2 equiv, 220.0 mmol) were charged into a 1-L jacketed reactor with the temperature set to 15 °C. Pivaloyl chloride (13.87 g, 1.15 equiv, 115.0 mmol) was added slowly. The temperature increased to 36 °C. The reaction mixture was stirred for 20 hours at 35–37 °C. After completion of the reaction, propan-2-ol (159 g, 200 mL, 26.5 equiv, 2.65 mol) was added to the mixture, and the mixture was concentrated by vacuum distillation. The slurry was cooled to 10 °C, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed with additional cold propan-2-ol (159 g, 200 mL, 26.5 equiv, 2.65 mol), and the solids were dried in a vacuum oven at 45–50 °C overnight to afford N-ethyl-3- (methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3, 31.2 g, 91.9 mmol, 91.9%) as a light-yellow solid. EXAMPLE 6

[0046] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)(pyridin-3-yl)thiazol-5-amine (S1, 35 g, 1 equiv, 165 mmol), dichloromethane (370 g, 280 mL) and 3-methylpyridine (34.2 g, 2.2 equiv, 364 mmol) were charged into a 500-mL jacketed reactor with a jacket temperature set to 10 °C. Pivaloyl chloride (23.2 g, 1.15 equiv, 190 mmol) was charged using a peristaltic pump while maintaining the reaction temperature between 10–15 °C. Following the addition, the jacket temperature was increased to 35 °C. The reaction mixture was stirred for 20 hours. After completion of the reaction, the mixture was concentrated by vacuum distillation until the slurry volume reached about 200 mL. Propan-2-ol (220 g, 280 mL) was added to the mixture, and the mixture was concentrated by vacuum distillation. The mixture was cooled to 0–5 °C, maintained at 0–5 °C for 1 hour, and filtered. The wet cake was washed with additional propan-2-ol (78.6 g, 100 mL; x2). The solid was dried in a vacuum oven at 60–65 °C overnight to afford N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3, 51.6 g, 150.7 mmol, 91.1%) as a light-yellow solid. EXAMPLE 7

[0048] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3), (methylsulfonyl)propanoic acid (S2, 0.837 g, 1.1 equiv, 5.5 mmol), dichloromethane (10 mL)and 3-methylpyridine (1.02 g, 2.2 equiv, 11.0 were charged into a 20 mL flask with a bath temperature set to 10 °C. Pivalic anhydride (1.07 g, 1.1 equiv, 5.5 mmol) was added slowly. The temperature increased to 36 °C. The reaction mixture was stirred for 40 hours at 35–37 °C. After completion of the reaction [note: the reaction was stopped after ~80% conversion due to the delay of full conversion], propan-2-ol (10 mL) was added to the mixture and the mixture was concentrated by vacuum distillation. The slurry was cooled to 10 °C, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed with additional cold propan-2-ol (2 mL). The solid was dried in a vacuum oven at 45–50 °C overnight to afford N-ethyl-3-(methylsulfonyl)-N-(2- (pyridin-3-yl)thiazol-5-yl)propanamide (1.03 g, 3.03 mmol, 60.7%) as a light-yellow solid.1H NMR data were consistent with S3. Analytical data were consistent with reference.EXAMPLE 8

[0050] Synthesis and Isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3)1.00 mmol), 3-(methylsulfonyl)propanoic acid (167 mg, 1.1 equiv, 1.10 mmol), dichloromethane (6.60 g, 5.00 mL, 77.7 equiv, 77.7 mmol), and 3-methylpyridine (615 mg, 6.6 equiv, 6.60 mmol) were charged into a 25 mL vial at 5 °C (ice bath). Pivaloyl chloride (139 mg, 1.15 equiv, 1.15 mmol) was added slowly. The temperature increased to 36 °C. The reaction mixture was stirred for 20 hours at 35–37 °C. After completion of the reaction, propan-2-ol (4.0 g, 5.00 mL, 66 equiv, 66 mmol) was added to the mixture and the mixture was concentrated. The slurry was cooled to 10 °C, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed with additional cold propan-2-ol, and the solids were dried in a vacuum oven at 45–50 °C overnight toafford N-ethyl-3-(methylsulfonyl)-N-(2- 3-yl)thiazol-5-yl)propanamide (330 mg, 972 μmol, 97.2%) as a light-yellow solid. EXAMPLE 9

[0052] Synthesis of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3)3-yl)thiazol-5-amine (2.05 g, 1 equiv, 10.0 mmol), dichloromethane (20.0 mL) and 3- methylpyridine (2.05 g, 2.2 equiv, 22.0 mmol) were charged into a 25-mL vial. ^Pivaloyl chloride (1.33 g, 1.1 equiv, 11.0 mmol) was charged slowly. Following the addition, the reaction mixture was stirred for 20 hours at 35 °C. After completion of the reaction, water (40.0 mL) and additional dichloromethane (20.0 mL) were added for layer separation. The (top) aqueous layer was removed. To the organic layer was charged aqueous hydrochloric acid (1 N, 40 mL). The (bottom) organic layer was removed to afford the product, N-ethyl-3-(methylsulfonyl)-N-(2- (pyridin-3-yl)thiazol-5-yl)propanamide (S3, 49.3 g, 7.60 mmol, 76.0%, 5.23 wt%) as a solution in aqueous HCl solution (which could be used as is).

[0054] Consequently, in light of the above the following additional, non-exhaustive, details (D) are provided. 1D. A one-step process to prepare N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S3) comprising: coupling N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1) or N-ethyl-2-(pyridin-3-yl)thiazol- 5-amine dihydrochloride (S1-HCl) with 3-(methylsulfonyl)propanoic acid (S2) in the presence of a carboxylic acid activator, a base, and a solventisolated as the free base. 2Db. The process according to 1D, wherein the process is conducted with S1 that has been isolated as the dihydrochloride salt (S1-HCl). 3D. The process according to any one of 1D–2Db, wherein from about 1 mole to about 1.175 moles of S2 per mole of S1 or S1-HCl is used. 4D. The process according to any one of 1D–2Db, wherein from about 1.05 moles to about 1.15 moles of S2 per mole of S1 or S1-HCl is used. 5D. The process according to any one of 1D–4D, wherein the carboxylic acid activator is pivalic anhydride or pivaloyl chloride. 6D. The process according to any one of 1D–5D, wherein from about 1 mole to about 1.5 moles of carboxylic acid activator per mole of S1 or S1-HCl is used. 7D. The process according to any one of 1D–5D, wherein from about 1.02 moles to about 1.2 moles of carboxylic acid activator per mole of S1 or S1-HCl is used. 8D. The process according to any one of 1D–7D, wherein the base is pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N- diisopropylethylamine (“DIPEA”), N-methylimidazole (“NMI”), or triethylamine (“Et3N”). 9D. The process according to any one of 1D–8D, wherein from about 1 mole to about 3 moles of base per mole of S1 is used.10D. The process according to any one of wherein from about 1.1 moles to about 2.3 moles of base per mole of S1 is used. 11D. The process according to any one of 1D–8D, wherein from about 1 mole to about 8 moles of base per mole of S1-HCl is used. 12D. The process according to any one of 1D–8D, wherein from about 3.5 moles to about 7 moles of base per mole of S1-HCl is used. 13D. The process according to any one of 1D–12D, wherein the solvent is ethyl acetate (“EtOAc”), isobutyl acetate (“i-BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), benzonitrile (“PhCN”), toluene (“PhCH3”), or mixtures thereof. 14D. The process according to any one of 1D–13D, wherein the coupling is conducted at temperatures from about 5 °C to about 50 °C. 15D. The process according to any one of 1D–13D, wherein the coupling is conducted at temperatures from about 10 °C to about 40 °C. 16D. The process according to any one of 1D–15D, wherein the coupling is conducted at a concentration of S1 or S1-HCl of from about 5 weight percent (wt%) to about 15 wt%. 17D. The process according to any one of 1D–15D, wherein the coupling is conducted at a concentration of S1 or S1-HCl of from about 5.0 weight percent (wt%) to about 10 wt%. 18D. The process according to any one of 1D–17D, wherein the product of the process, S3, is isolated from an isolation solvent. 19D. The process according to any one of 1D–17D, wherein the product of the process, S3, is not isolated from an isolation solvent and used without further manipulation. 20D. The process according to 18D or 19D, wherein the isolation solvent is water, aqueous hydrochloric acid, methanol, ethanol, propan-2-ol, ethyl acetate (“EtOAc”), isobutyl acetate (“i- BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2- pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), benzonitrile (“PhCN”), or mixtures thereof.

[0055] All references, including 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.

[0056] The use of the terms “a” and “an” and “the” and “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 clearly 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.

[0057] 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 variationsthereof is encompassed by the invention indicated herein or otherwise clearly contradicted by context.

Claims

WE CLAIM:

1. A one-step process to prepare N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3- yl)thiazol-5-yl)propanamide (S3) comprising: coupling N-ethyl-2-(pyridin-3-yl)thiazol-5-amine (S1) or N-ethyl-2-(pyridin-3-yl)thiazol- 5-amine dihydrochloride (S1-HCl) with 3-(methylsulfonyl)propanoic acid (S2) in the presence of a carboxylic acid activator, a base, and a solvent .

2. The process according to claim 1, wherein the process is conducted with S1 that has been isolated as the free base.

3. The process according to claim 1, wherein the process is conducted with S1 that has been isolated as the dihydrochloride salt (S1-HCl).

4. The process according to any one of claims 1–3, wherein from about 1 mole to about 1.175 moles of S2 per mole of S1 or S1-HCl, or from about 1.05 moles to about 1.15 moles of S2 per mole of S1 or S1-HCl is used.

5. The process according to any one of claims 1–4, wherein the carboxylic acid activator is pivalic anhydride or pivaloyl chloride.

6. The process according to any of claims 1–5, wherein from about 1 mole to about 1.5 moles of carboxylic acid activator per mole of S1 or S1-HCl, or from about 1.02 moles to about 1.2 moles of carboxylic acid activator per mole of S1 or S1-HCl is used.

7. The process according to any one of claims 1–6, wherein the base is pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N- diisopropylethylamine (“DIPEA”), N-methylimidazole (“NMI”), or triethylamine (“Et3N”).

8. The process according to any one of claims 1–7, wherein from about 1 mole to about 3 moles of base per mole of S1 or from about 1.1 moles to about 2.3 moles of base per mole of S1 is used.

9. The process according to any one of claims 1–7, wherein from about 1 mole to about 8 moles of base per mole of S1-HCl, or from about 3.5 moles to about 7 moles of base per mole of S1 is used.

10. The process according to any one of claims 1–9, wherein the solvent is ethyl acetate (“EtOAc”), isobutyl acetate (“i-BuOAc”), tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), benzonitrile (“PhCN”), toluene (“PhCH3”), or mixtures thereof.

11. The process according to any one of claims 1–10, wherein the coupling is conducted at temperatures from about 5 °C to about 50 °C or from about 10 °C to about 40 °C.

12. The process according to any one of claims 1–11, wherein the coupling is conducted at a concentration of S1 or S1-HCl of 5 weight percent (wt%) to about 15 wt% or from about 5.0 weight percent (wt%) to about 10 wt%.

13. The process according to any one of claims 1–12, wherein the N-ethyl-3- (methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3) is isolated from an isolation solvent.

14. The process according to any of claims 1–12, wherein the N-ethyl-3- (methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S3) is not isolated from an isolation solvent and used without further manipulation.

15. The process according to any one of claims 1–14, wherein the isolation solvent is water, aqueous hydrochloric acid, aqueous formic acid, methanol, ethanol, propan-2-ol, ethyl acetate (“EtOAc”), isobutyl acetate (“i-BuOAc”), tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), 1-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), dichloroethane ("DCE”), chloroform (“CHCl3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), benzonitrile (“PhCN”), or mixtures thereof.

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