Processes related to formation of n-(4-chloro-2-(pyridin-3-YL)thiazol-5-YL)-n-ethyl-3-(methylsulfonyl)propanamide

Abstract

A continuous process to prepare N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3- (methylsulfonyl)propanamide (S2) is provided.

Description

PROCESSES RELATED TO FORMATION OF A-(4-CHLORO-2-(PYRIDIN-3- YL)THIAZOL-5-YL)-A-ETHYL-3-(METHYLSULFONYL)PROP AN AMIDECROSS REFERENCE TO RELATED TO APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.63 / 680,275 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 WO2010 / 129497; WO 2013 / 184475; WO 2013 / 184476; WO 2013 / 184480; and PCT / US2022 / 074322.SUMMARY

[0003] A continuous process to prepare M(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-7V-ethyl-3-(methylsulfonyl)propanamide (S2) comprising: combining A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (SI) and a chlorinating agent in the presence of a solvent is provided.

[0004] Additionally provided is a process wherein the reactor space time is from about 1 second to about 60 seconds.—Internal Use —DETAILED DESCRIPTION

[0005] Provided herein are continuous processes related to the formation of / V-(4-chloro-2- (pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (also known as “S2” herein, shown below) from the molecule of SI.S2

[0006] Additionally provided is a process wherein the reactor space time is from about 1 second to 60 seconds.

[0007] The molecule, A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (also known as “SI” herein), having the following formula has been disclosed in PCT / US2024 / 014736.S1

[0008] Definitions

[0009] 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] Continuous flow”, “flow”, “continuous formation”, “continuous process”, or other derivative terms (e.g. “under flow conditions”) as used herein means methods that produce a minimum amount of a reactive intermediate at any given time and provide reduced cycle times in—Internal Use —comparison to conventional methods. For example, U.S. Patent 9,145,428 B2 describes methods and systems using continuous flow.

[0013] Cycle time is the average net production time of a product.

[0014] Space time in a reactor is the time required to process one reactor volume of feed. It is equal to the reactor volume divided by the total volumetric feed rate. (O. Levenspiel, Chemical Reaction Engineering, Second Ed. (1972))

[0015] “Throughput” or “molecular throughput” is the amount of feed that is put through a process. (Collins Dictionary https: / / www.collinsdictionary.com / ). Throughput is measured in moles per liter per hour (mol / L / h).

[0016] Throughput may also be referred to as “product generation rate”, which is measured in moles per hour (mol / h) on a one-liter (1-L) reactor volume basis.

[0017] Scheme One

[0018] The reaction in Scheme One is conducted in the presence of a chlorinating agent. JV- Ethyl-3-(methylsulfonyl)-7V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (SI) is chlorinated to form JV-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)- / V-ethyl-3-(methylsulfonyl)propanamide (S2). In general, about 1 mole to about 2 moles of chlorinating agent per mole of SI may be used; more preferably, about 1 mole to about 1.6 moles of chlorinating agent per mole of SI may be used. Examples of chlorinating agents include chlorine, A-chlorosuccinimide (“NCS”), 1, 1,3,3- dichlorodimethylhydantoin (“DCDMH”), 7V-chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), / e7 -butylhypochlorite, chloramine-T, / -chlorobenzotriazole (“NCBT”), trichloroisocyanuric acid (“TCCA”), and sodium hypochlorite. Chlorine is preferred.

[0019] The reaction in Scheme One is conducted 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”), dibutyl—Internal Use —ether, ethyl acetate (“EtOAc”), butyl acetate (“zz-BuOAc”), and isobutyl acetate (“z-BuOAc”). Examples of polar protic solvents are / / -butanol (“ / / -BuOH”), isopropanol or propan-2-ol (“z- PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid (“AcOH”), formic acid (“HCOOH”), and aqueous hydrochloric acid (“HQ”). Optionally, mixtures of solvents may be used. Aqueous HC1 or formic acid (“HCOOH”) is preferred.

[0020] The reaction in Scheme One may be conducted in a continuous process, with the reactor space time from about 1 second to about 60 seconds.

[0021] 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 10 °C to about 60 °C may be used, preferably temperatures from about 15 °C to 45 °C may be used. Currently, pressures from ambient (usually 101) to 450 kilopascal (kPa) may be used; preferably pressures from ambient (usually 101) to about 300 kPa may be used.

[0022] In one embodiment, the reaction in Scheme One may be conducted in a reactor under flow conditions. In one embodiment, the reactor may contain static or dynamic mixing units

[0023] In one embodiment, a reducing agent may be added to the resulting mixture from Scheme One. Examples of reducing agents include sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, and sulfur dioxide. Sodium bisulfite is preferred. In one embodiment, the sodium bisulfite is used as an aqueous solution. In another embodiment, the addition of the reducing agent may occur under flow conditions. In a further embodiment, the addition of the reducing agent may occur under flow conditions using static or dynamic mixing units.

[0024] In one embodiment, the reaction in Scheme One may be quenched with a reducing agent. Examples of reducing agents include sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, and sulfur dioxide. Sodium bisulfite is preferred. In one embodiment, the sodium bisulfite is used as an aqueous solution. In another embodiment, the reaction may be quenched under flow conditions. In a further embodiment, the reaction may be quenched under flow conditions using static or dynamic mixing units.—Internal Use —

[0025] In one embodiment, a base may be added to the resulting mixture from Scheme One. Examples of bases are organic bases and inorganic bases. Examples of organic bases are pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3 -methylpyridine, N,N- diisopropylethylamine (“DIPEA”), triethanolamine (“(HOCH 2 CH2)3N”), and tri ethylamine (“EtsN”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCOi”), sodium citrate, disodium phosphate (“Na2HPO4”), and sodium hydroxide (“NaOH”). Sodium hydroxide (“NaOH”) is preferred. The addition of the base results in a change in the pH of the mixture from between about pH 3 and about pH 7, preferably between about pH 5 and about pH 7. In another embodiment, the base may be added to the resulting mixture from Scheme One under flow conditions. In a further embodiment, the base may be added to the resulting mixture from Scheme One under flow conditions in a continuously stirred tank reactor (CTSR) or a tubular reactor.

[0026] In one embodiment, the pH of the reaction in Scheme One may be adjusted by the addition 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-methylpyridine, 3- methylpyridine, MA-diisopropylcthylamine (“DIPEA”), triethanolamine (“(HOCH 2 CH2)3N”), and triethylamine (“EtsN”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCOs”), sodium citrate, disodium phosphate (“Na2HPO4”), and sodium hydroxide (“NaOH”). Sodium hydroxide (“NaOH”) is preferred. The pH is adjusted to between about pH 3 and about pH 7, preferably between about pH 5 and about pH 7. In another embodiment, the pH may be adjusted under flow conditions. In a further embodiment, the pH may be adjusted under flow conditions in a continuously stirred tank reactor (CTSR) or a tubular reactor.

[0027] In one embodiment, the product of the reaction in Scheme One, S2, may be isolated in solution via continuous extraction. In a further embodiment, S2 may be crystallized from the solution. In another embodiment, S2 may be crystallized from the solution in a batch process. In another embodiment, S2 may be crystallized from the solution in a continuous process. In one—Internal Use —embodiment, the solvent in the solution may be ethyl acetate, butyl acetate, isobutyl acetate, 2- methyltetrahydrofuran, dichloromethane, dibutyl ether, methylcyclohexane, hexane, heptane, octane, nonane, decane, or a mixture thereof.

[0028] Examples provided herein are not exhaustive and should not be construed as limiting.COMPARATIVE EXAMPLE

[0029] Synthesis and Isolation of JV-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-7V-ethyl-3-(methylsulfonyl)propanamide (S2)

[0030] V-Ethyl-3-(methylsulfonyl)-jV-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (SI, 30.1 g, 100 wt%, 89 mmol) was added to a 1-L jacketed reactor with overhead agitator. Water (157.8 g, 8.8 mol) was added, forming a slurry. Aqueous HC1 (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 added slowly through a glass tube submerged under the liquid surface over 50 minutes. Upon reaction completion, 36 wt% aqueous sodium bisulfite (12.4 g, 48 mmol) was added, and the mixture was stirred for 60 minutes. Ethyl acetate (131.4 g, 1.49 mol) was added to the reactor. Aqueous sodium hydroxide (50 wt%, 25.5 g, 319 mmol) was added to bring the pH up to 7. The reactor was warmed to 35 °C. The phases were allowed to settle and separate. The organic layer was washed with water (69.8 g, 3.87 mol) and was cooled to 30 °C. S2 (0.15 g, 4.0 mmol) was added as seed to induce nucleation. The seeded mixture was held at 30 °C for 2 hours.Heptane (147.1 g, 1.47 mol) was added dropwise over 2 hours. The slurry was cooled to -10 °C over 1 hour and held for an additional 1 hour before fdtration. The wet cake was washed once with heptane (44.8 g, 447 mmol). The solid was dried in the vacuum oven overnight to afford N- (4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-V-ethyl-3-(methylsulfonyl)propanamide (S2, 25.4 g, 76%—Internal Use —yield). The approximate product generation rate for S2 for the reaction with chlorine gas was 0.4 moles per hour (mol / h) on a 1-L reactor volume basis.EXAMPLE 1

[0031] Synthesis of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S2)

[0032] A stock solution of SI was prepared by combining SI (170 grams (g), 96.6 weight percent (wt%), 1.00 equivalent (equiv), 484 millimoles (mmol)), water (1.56 kilograms (kg), 1.6 liters (L), 179 equiv, 86.4 moles (mol)), and hydrochloric acid (HC1, aqueous, 169 g, 156 milliliters (mL), 20.0 wt%, 1.92 equiv, 926 mmol). The stock solution of SI (1.89 kg, 1.87 L, 8.7 wt%, 1 equiv, 482 mmol) and chlorine gas (49.5 g, 1.45 equiv, 698 mmol) were charged to a 42- milliliter reactor with static mixing units at 45 °C, 101-239 kPa, and reactor space time of 12 seconds (sec). The product was quenched continuously with sodium bisulfite (aqueous, 146 g, 109 mL, 20.1 wt%, 0.584 equiv, 281 mmol) in a reactor with static mixing units at 45 °C and 101-239 kPa. The quenched product was transferred to a continuous stirred tank reactor, where ethyl acetate (1.86 kg, 2.06 L, 43.8 equiv, 21.1 mol) and sodium hydroxide (aqueous, 456 g, 374 mL, 20.0 wt%, 4.73 equiv, 2.28 mol) were charged continuously in order to maintain pH between 5 and 7. The biphasic mixture was transferred to a settling tank. The aqueous layer was continuously removed. The organic layer was continuously collected. The product solution of S2 (in ethyl acetate, 1.94 kg, 405 mmol, 84% yield, 7.8 wt%) was held in reserve for crystallization. The product generation rate for S2 was 13 mol / h on a 1-L reactor volume basis.—Internal Use —EXAMPLE 2

[0033] Synthesis of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S2)S1 S2

[0034] A stock solution of SI was prepared by combining SI (1.50 kg, 94.8 wt%, 1.01 equiv, 4.19 mol), water (13.8 kg, 13.8 L, 185 equiv, 766 mol), and HC1 (aqueous, 1.33 kg, 20.0 wt%, 1.77 equiv, 7.32 mol) at 20 °C. The stock solution of SI (16.4 kg, 16.2 L, 8.55 wt%, 1 equiv, 4.12 mol) and chlorine gas (450 g, 1.54 equiv, 6.34 mol) were charged to a 42-milliliter reactor with static mixing units at 45 °C, 101-239 kPa, and reactor space time of 13 seconds (sec). The product was quenched continuously with sodium bisulfite (aqueous, 1.14 kg, 850 mL, 20.0 wt%, 0.532 equiv, 2.19 mol) in a reactor with static mixing units at 45 °C and 101-239 kPa. The quenched product was transferred to a continuous stirred tank reactor, where ethyl acetate (13.5 kg, 14.9 L, 37.1 equiv, 153 mol) and sodium hydroxide (aqueous, 3.50 kg, 2.87 L, 20.0 wt%, 4.25 equiv, 17.5 mol) were charged continuously in order to maintain pH between 5 and 7. The biphasic mixture was transferred to a settling tank. The aqueous layer was continuously removed. The organic layer (in ethyl acetate, 14.3 kg, 3.6 mol, 88% yield, 9.5 wt%) was continuously collected, concentrated via rotary evaporation to >20 wt%, and held in reserve for crystallization. The product generation rate for S2 was 13 mol / h on a 1-L reactor volume basis.EXAMPLE 3

[0035] Synthesis of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S2)—Internal Use —

[0036] A stock solution of SI was prepared by combining SI (1.50 kg, 94.8 wt%, 1.00 equiv, 4.19 mol), water (13.8 kg, 13.8 L, 183 equiv, 766 mol), and HC1 (aqueous, 1.33 kg, 20.0 wt%, 1.75 equiv, 7.32 mol) at 20 °C. The stock solution of SI (16.6 kg, 16.5 L, 8.55 wt%, 1 equiv, 4.19 mol) and chlorine gas (451 g, 1.52 equiv, 6.36 mol) were charged to a 42-milliliter reactor with static mixing units at 45 °C, 101-239 kPa, and reactor space time of 13 seconds (sec). The product was quenched continuously with sodium bisulfite (aqueous, 1.18 kg, 884 mL, 20.0 wt%, 0.544 equiv, 2.28 mol) in a reactor with static mixing units at 45 °C and 101-239 kPa. The quenched product was transferred to a continuous stirred tank reactor, where ethyl acetate (13.8 kg, 15.3 L, 37.4 equiv, 157 mol) and sodium hydroxide (aqueous, 3.57 kg, 2.93 L, 20.0 wt%, 4.27 equiv, 17.9 mol) were charged continuously in order to maintain pH between 5 and 7. The biphasic mixture was transferred to a settling tank. The aqueous layer was continuously removed. The organic layer (in ethyl acetate, 14.6 kg, 3.8 mol, 90% yield, 9.6 wt%) was continuously collected, concentrated via rotary evaporation to >20 wt%, and held in reserve for crystallization. The product generation rate for S2 was 13 mol / h on a 1-L reactor volume basis.EXAMPLE 4

[0037] Crystallization of Ar-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-Ar-ethyl-3-(methyl sulfonyl)propanami de (S2)S2—Internal Use —

[0038] The concentrated solutions of S2 from Examples 2 and 3 (11.9 kg, 7.39 mol, 23.2 wt%) were combined in a 50-liter reactor. Ethyl acetate (3.7 kg, 4.1 L, 5.7 equiv, 42 mol) was charged to the reactor. The combined solution was heated to 48 °C, then cooled to 30 °C. S2 (28 g, 0.010 equiv, 0.074 mol) was combined with ethyl acetate (68 g, 76 mL, 0.10 equiv, 0.77 mol). The combined slurry was charged as seed. The mixture was cooled to 28 °C and held for 16 hours. The mixture was then cooled to 17 °C over 4 hours. Heptane (13.3 kg, 19.4 L, 18.0 equiv, 133 mol) was added over 21 hours. The solution was cooled from 17 °C to 10 °C over 1 hour and held for an additional 2 hours. The mixture was fdtered and washed with heptane (7.4 kg, 11 L, 9.9 equiv, 73 mol). The solids were dried in air for 48 hours then transferred to a vacuum oven at 50 °C and dried for 48 hours to afford S2 as a light yellow solid (2.70 kg, 6.95 mol, 96.4 wt%, 94% crystallization yield, 83% combined yield for Examples 2, 3, and 4).EXAMPLE 5

[0039] Synthesis ofJV-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-JV-ethyl-3-(methylsulfonyl)propanamide (S2)

[0040] A stock solution of SI was prepared by combining SI (15.0 g, 1 equiv, 44.2 mmol), and acetic acid (158 g, 150 mL, 59.3 equiv, 2.62 mol). In a series of screening experiments, the stock solution of SI (8.7 wt%, 1 equiv) and chlorine gas (0.95-1.05 equiv) were charged to an 8- milliliter reactor with static mixing units at 25-45 °C and reactor space time of 5-60 seconds (sec). Conversion of SI at the exit of the reactor was between 75% and 100% and yield of S2 in solution was between 70% and 89% for all experiments. When the stock solution of SI (8.7 wt%, 1 equiv) and chlorine gas (1.05 equiv.) were charged to the reactor at 25 °C and reactor space time of 12 seconds (sec), the conversion of SI was 100% and the yield of S2 in solution was 89%.—Internal Use —EXAMPLE 6

[0041] Synthesis of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methyl sulfonyl)propanami de (S2)

[0042] A stock solution of SI was prepared by combining SI (200 g, 1 equiv, 0.589 mol), water (844 g, 844 mL, 80.3 equiv, 46.8 mol), and HC1 (aqueous, 20 wt%, 172 g, 160 mL, 1.62 equiv, 0.944 mol). The stock solution of SI (1203 g, 1.2 L, 16 wt%, 1 equiv) and chlorine gas (62 g, 1.5 equiv, 0.87 mol) were charged to a 42-milliliter reactor with static mixing units at 45 °C and reactor space time of 5 seconds (sec). The product was neutralized by slow addition of sodium hydroxide (aqueous, 160 g, 0.10 L, 50 wt%, 3.4 equiv, 2.0 mol) and simultaneously extracted into ethyl acetate (902 g, 1.00 L, 17.6 equiv, 10.2 mol). The organic layer containing S2 in ethyl acetate was washed with water (1000 g, 1.00 L, 95.2 equiv, 55.5 mol). The organic layer (in ethyl acetate, 971 g, 18.9 wt%, 88% yield) was held in reserve for crystallization. The product generation rate for S2 was 18 mol / h on a 1-L reactor volume basis.EXAMPLE 7

[0043] Crystallization of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S2)S2—Internal Use —

[0044] The solution from Example 6 (971 g, 18.9 wt%, 1 equiv, 0.49 mol) was heated to SO- 55 °C and fed continuously with heptane (1.0 kg, 1.5 L, 21 equiv, 10.3 mol) to a mixed- suspension mixed-product removal (MSMPR) continuous crystallization unit, wherein the slurry was first cooled to 30 °C, then to 5 °C, and subsequently transferred to a filter. The product was filtered and dried at 40 °C to afford S2 as a light brown solid (145 g, 96.8 wt%, 77% yield).EXAMPLE 8

[0045] Synthesis of Ar-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S2)S1 S2

[0046] A stock solution of SI was prepared by combining SI (400 g, 100 wt%, 1.00 equiv, 1.18 mol), water (531 g, 0.54 liters (L), 25.0 equiv, 29.5 mol), and formic acid (657 g, 562 mb, 12.1 equiv, 14.3 mol). The stock solution of SI was filtered. The stock solution of SI (1.58 kg, 1.26 L, 25.2 wt%, 1 equiv, 1.17 mol) and chlorine gas (91.3 g, 1.10 equiv, 1.29 mol) were charged to a 25-milliliter reactor with static mixing units at 35 °C, 101-218 kPa, and reactor space time of 3 seconds. The product was quenched continuously with sodium bisulfite (aqueous, 175 g, 130 mL, 20.0 wt%, 0.286 equiv, 335 mmol) in a reactor with static mixing units at 35 °C and 101-218 kPa. The quenched product was transferred to a continuous stirred tank reactor, where ethyl acetate (4.08 kg, 4.53 L, 40.9 equiv, 46.3 mol) and sodium hydroxide (aqueous, 2.54 kg, 2.00 L, 25.0 wt%, 14.0 equiv, 15.9 mol) were charged continuously in order to maintain pH between 5 and 6. The biphasic mixture was transferred to a settling tank. The aqueous layer was removed. The product solution of S2 (in ethyl acetate, 4.56 kg, 1.16 mol, 99% yield, 9.4 wt%) was held in reserve for crystallization. The product generation rate for S2 was 53 mol / h on a 1-L reactor volume basis.—Internal Use —

[0047] Consequently, in light of the above the following additional, non-exhaustive, details (D) are provided.ID. A continuous process to prepare A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl )-A-ethyl-3- (methylsulfonyl)propanamide (S2) comprising: combining A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (SI) and a chlorinating agent in the presence of a solvent2D. The process according to ID, wherein the reactor space time is from about 1 second to about 60 seconds.3D The process according to ID or 2D, wherein from about 1 mole to about 2 moles of chlorinating agent per mole of SI is used.4D. The process according to ID or 2D, wherein from about 1 mole to about 1.6 moles of chlorinating agent per mole of SI is used.5D. The process according to any one of 1D-4D, wherein the chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), N- chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), Zcz'Z-butylhypochlorite, chloramine-T, / V-chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), or sodium hypochlorite.6D. The process according to 5D, wherein the chlorinating agent is chlorine.7D. The process according to any one of 1D-6D, wherein the solvent is 1,4-dioxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), di chloromethane (“DCM”), dibutyl ether, ethyl acetate (“EtOAc”), butyl acetate (“z?-BuOAc”), isobutyl acetate (“ / -BuOAc”), / / -butanol (“w-BuOH”), isopropanol or propan-2-ol (“z-PrOH”), n- propanol (“«-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“EEO”), acetic acid (“AcOH”), formic acid (“HCOOH”), aqueous hydrochloric acid (“140”), or mixtures thereof.—Internal Use —8D. The process according to 7D, wherein the solvent is aqueous hydrochloric acid (“HC1”) or formic acid (“HCOOH”).9D. The process according to any one of 1D-8D, wherein the process is conducted at a temperature from about 10 °C to about 60 °C.10D. The process according to 9D, wherein the process is conducted at a temperature from about 15 °C to about 45 °C.1 ID. The process according to any one of 1D-10D, wherein the process is conducted at a pressure from about ambient (usually 101 kilopascal) to about 450 kilopascal (kPa).12D. The process according to 1 ID, wherein the process is conducted at a pressure from about ambient (usually 101 kilopascal) to about 300 kilopascal (kPa).13D. The process according to any one of 1D-12D, wherein the process is quenched with a reducing agent, wherein the reducing agent is sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, or sulfur dioxide.14D. The process according to 13D, wherein the reducing agent is sodium bisulfite.15D. The process according to 14D, wherein the sodium bisulfite is in aqueous solution.16D. The process according to any one of 13D-15D, wherein the process is quenched under flow conditions using static or dynamic mixing units.17D. The process according to any one of 1D-16D, wherein the pH of the process is adjusted by addition of a base, wherein the base is pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3 -methylpyridine, A,A-diisopropylethylamine (“DIPEA”), triethanolamine (“(HOCH 2 CH2)3N”), tri ethylamine (“EtsN”), potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCO.i”), sodium citrate, disodium phosphate (“Na2HPO4”), or sodium hydroxide (“NaOH”).18D. The process according to 17D, wherein the base is sodium hydroxide.19D. The process according to any one of 17D-18D, wherein the pH of the process is adjusted to between about pH 3 and about pH 7.20D. The process according to 19D, wherein the pH of the process is adjusted to between about pH 5 and about pH 7.—Internal Use —2 ID. The process according to any one of 17D-20D, wherein the pH of the process is adjusted in a continuously stirred tank reactor or a tubular reactor.22D. The process according to any one of 1D-21D, wherein the product of the process (S2) is isolated in solution via continuous extraction.23D. The process according to 22D, wherein the product of the process (S2) is crystallized from the solution.24D. The process according to 23D, wherein the product of the process (S2) is crystallized from the solution in a batch process.25D. The process according to 23D, wherein the product of the process (S2) is crystallized from the solution in a continuous process.26D. The process according to 25D, wherein the continuous crystallization process uses a mixed-suspension mixed-product removal crystallization unit.27D. The process according to any one of 22D-26D, wherein the solution comprises a solvent. 28D. The process according to 27D, wherein the solvent is ethyl acetate, butyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, dichloromethane, dibutyl ether, methylcyclohexane, hexane, heptane, octane, nonane, decane, or a mixture thereof.29D. The process according to any one of 1D-12D, wherein a reducing agent is added to the resulting mixture from any one of 1D-12D, wherein the reducing agent is sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, or sulfur dioxide.30D. The process according to 29D, wherein the reducing agent is sodium bisulfite.3 ID. The process according to 30D, wherein the sodium bisulfite is in aqueous solution.32D. The process according to any one of 29D-3 ID, wherein the addition of the reducing agent occurs under flow conditions using static or dynamic mixing units.33D. The process according to any one of 1D-12D or 29D-32D, wherein a base is added to the resulting mixture from any one of 1D-12D or 29D-32D, wherein the base is pyridine, 2,6- dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N- di isopropyl ethyl amine (“DIPEA”), triethanolamine (“(HOCH 2 CH2)aN”), triethylamine (“EtaN”), potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium—Internal Use —hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCCh”), sodium citrate, disodium phosphate (“Na2HPO4”), or sodium hydroxide (“NaOH”).34D. The process according to 33D, wherein the base is sodium hydroxide.35D. The process according to any one of 33D-34D, wherein the addition of the base results in a change in the pH of the resulting mixture from any one of 1D-12D or 29D-32D from between about pH 3 to about pH 7.36D. The process according to 35D, wherein the addition of the base results in a change in the pH of the resulting mixture from any one of 1D-12D or 29D-32D from between about pH 5 to about pH 7.37D. The process according to any one of 33D-36D, wherein the base is added in a continuously stirred tank reactor or a tubular reactor.38D. The process according to any one of 1D-12D or 29D-37D, wherein the JV-(4-chloro-2- (pyridin-3-yl)thiazol-5-yl)-A'-ethyl-3-(methylsulfonyl)propanamide (S2) is isolated in solution via continuous extraction.39D. The process according to 38D, wherein the 7V-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-Ar- ethyl-3-(methylsulfonyl)propanamide (S2) is crystallized from the solution.40D. The process according to 39D, wherein the V-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-7V- ethyl-3-(methylsulfonyl)propanamide (S2) is crystallized from the solution in a batch process.41D. The process according to 39D, wherein the V-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-7V- ethyl-3-(methylsulfonyl)propanamide (S2) is crystallized from the solution in a continuous process.42D. The process according to 4 ID, wherein the continuous crystallization process uses a mixed-suspension mixed-product removal crystallization unit.43D. The process according to any one of 38D-42D, wherein the solution comprises a solvent. 44D. The process according to 43D, wherein the solvent is ethyl acetate, butyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, dichloromethane, dibutyl ether, methylcyclohexane, hexane, heptane, octane, nonane, decane, or a mixture thereof.—Internal Use —

[0048] 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.

[0049] 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 may 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.

[0050] 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—Internal Use —thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.—Internal Use —

Claims

WE CLAIM:

1. A continuous process to prepare A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A- ethyl-3-(methylsulfonyl)propanamide (S2) comprising: combining A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (SI) and a chlorinating agent in the presence of a solvent2. The process according to claim 1, wherein the process is conducted in a reactor with space time from about 1 second to about 60 seconds.

3. The process according to claim 1 or claim 2, wherein from about 1 mole to about 2 moles of the chlorinating agent per mole of SI is used or from about 1 mole to about 1.6 moles of the chlorinating agent per mole of SI is used.

4. The process according to any one of claims 1-3, wherein the chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), N- chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), Zc / Z-butylhypochlorite, chloramine-T, A-chlorobenzotriazole (“NCBT”), trichloroisocyanuric acid (“TCCA”), or sodium hypochlorite.

5. The process according to claim 4, wherein the chlorinating agent is chlorine.

6. The process according to any one of claims 1-5, wherein the solvent is 1,4- dioxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”), butyl acetate (“n-BuOAc”), isobutyl acetate (“z-BuOAc”), zz-butanol (“zz-BuOH”), isopropanol (“z-PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid (“AcOH”), formic acid (“HCOOH”), aqueous hydrochloric acid (“HQ”), or mixtures thereof.—Internal Use —7. The process according to claim 6, wherein the solvent is aqueous hydrochloric acid (“HQ”) or formic acid (“HCOOH”).

8. The process according to any one of claims 1-7, wherein the process is conducted at a temperature from about 10 °C to about 60 °C or from about 15 °C to about 45 °C.

9. The process according to any one of claims 1-8, wherein the process is conducted at a pressure from about 101 kilopascal to about 450 kilopascal (kPa) or from about 101 kilopascal to about 300 kilopascal (kPa).

10. The process according to any one of claims 1-9, wherein a reducing agent is added to the resulting mixture from any one of claims 1-9, wherein the reducing agent is selected from the group consisting of sodium bisulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, and sulfur dioxide is added.

11. The process according to any one of claims 1-10, wherein the addition of the reducing agent occurs under flow conditions using static or dynamic mixing units.

12. The process according to any one of claims 1-11, wherein a base may be added to the resulting mixture from any one of claims 1-11, wherein the base is selected from the group consisting of pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3- methylpyridine, jV,A-diisopropylethylamine (“DIPEA”), triethanolamine (“(HOCH 2 CH2)3N”), triethylamine (“EtsN”), potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (‘“bfeCCh”), sodium bicarbonate (“NaHCOs”), sodium citrate, disodium phosphate (“Na2HPO4”), and sodium hydroxide (“NaOH”).

13. The process according to any one of claims 1-12, wherein the addition of the base results in a change in the pH of the resulting mixture from any one of claims 1-12 from between about pH 3 and about pH 7 or between about pH 5 and about pH 7.

14. The process according to any one of claims 1-13, wherein the base is added in a continuously stirred tank reactor or a tubular reactor.

15. The process according to any one of claims 1-14, wherein the A-(4-chloro-2- (pyridin-3-yl)thiazol-5-yl)-.V-ethyl-3-(methylsulfonyl)propanamide (S2) is isolated in solution via continuous extraction and optionally is crystallized from the solution.—Internal Use —

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