Preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone

Abstract

The present invention relates to a method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone.

Description

Field of the Invention

[0001] The present invention relates to a method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone. Background of the Invention

[0003] 2-Chloro-1-(2-chlorothiazol-5-yl)ethanone is a valuable intermediate in the synthesis of the pyridinium compounds known, inter alia, from WO 2014 / 164084 A1. These compounds exhibit excellent insecticidal properties.

[0004] WO 2018 / 197541 A1 and WO / 202654 A1 disclose synthetic routes for these pyridinium compounds, which include reacting chloro-(2-chlorothiazol-5-yl)magnesium material with 2-chloro-N-methoxy-N-methyl-acetamide to form 2-chloro-1-(2-chlorothiazol-5-yl)ethanone.

[0005] T. Chalopin et al., Second generation of thiazolylmannosides, Fim Hantagonists for E. coli-induced Crohn's disease, Org. Biomol. Chem., 2016, 14, 3913-3925 describe the synthesis of 1-(2-chlorothiazol-5-yl)ethanone from thiourea.

[0006] However, the prior art processes have several disadvantages such as high effluent loading and metal salt loading, low yield, low selectivity and the use of toxic solvents.

[0007] Therefore, the object of the present invention is to provide an economical process for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, which provides 2-chloro-1-(2-chlorothiazol-5-yl)ethanone with high overall yield, i.e. ≥85% or ≥80%, with high selectivity, and the process can be easily controlled. SUMMARY OF THE INVENTION

[0009] Surprisingly, it has been found that controlled cyclization of 1,3-bis(dimethylaminomethylene)thiourea and chloroacetone by addition of chloroacetone at a specific addition rate followed by acid treatment, Sandmeyer reaction and chlorination leads to the formation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone in high yield and selectivity within a reasonable process time.

[0010] Therefore, in one aspect, the present invention relates to a method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, which comprises at least the following steps:

[0011] a) cyclizing 1,3-bis(dimethylaminomethylene)thiourea with chloroacetone to form N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine,

[0012] b) subjecting (5-acetylthiazol-2-yl)-N,N-dimethylformamidine to at least one acid to form 1-(2-aminothiazol-5-yl)ethanone,

[0013] c) subjecting 1-(2-aminothiazol-5-yl)ethanone to a Sandmeyer reaction to form 1-(2-chlorothiazol-5-yl)ethanone, and

[0014] d) chlorinating 1-(2-chlorothiazol-5-yl)ethanone to form 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, wherein in step a) chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤8.0 vol. % / min, based on the total volume of chloroacetone.

[0015] Details

[0016] Before describing the compositions and formulations of the invention claimed in the present application, it should be understood that the present invention is not limited to the specific compositions and formulations described, as the compositions and formulations can generally vary. It should also be understood that the terminology used herein is not intended to be limiting, as the scope of the invention claimed in the present application is limited only by the appended claims.

[0017] If below, group is defined as including at least a certain number of embodiments, this means also including a group preferably consisting of only these embodiments. In addition, the terms "first", "second", "third" or "a", "b", "c" etc. in the specification and claims are used to distinguish similar elements, and are not necessarily used to describe order or chronological order. It should be understood that the terms used in this way are interchangeable where appropriate, and the embodiments of the invention claimed in the present application described herein can be operated in a sequence different from that described or shown herein. In the case of the step of method or purposes or determination, there is no time or time interval coherence between the steps, i.e., the steps can be carried out simultaneously or there can be a time interval of seconds, minutes, hours, days, weeks, months or even years between these steps, unless otherwise specified in the present application as described above or below.

[0018] In addition, ranges defined throughout the specification also include the endpoints, i.e., a range of 1-10 means that both 1 and 10 are included in the range. For the avoidance of doubt, applicants should be granted any equivalents under applicable law.

[0019] In the following paragraphs, different aspects of the invention claimed in the present application are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects, unless explicitly stated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0020] References to "one embodiment" or "an embodiment" throughout the specification mean that the specific features, structures or characteristics described in the embodiment are included in at least one embodiment of the invention claimed in the present application. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places in this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. In addition, the terms "preferably", "more preferably", "even more preferably", "most preferably" and "in particular" or similar terms used hereinafter are used in conjunction with optional features without limiting the alternative possibilities. Therefore, the features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way.

[0021] In addition, as those skilled in the art will appreciate from this disclosure, in one or more embodiments, specific features, structures or characteristics may be combined in any suitable manner. In addition, although some embodiments described herein include some but not other features in other embodiments, the combination of features of different embodiments is meant to be within the scope of the invention claimed in this application, and to form different embodiments, as understood by those skilled in the art. For example, in the appended claims, any claimed embodiment may be used in any combination.

[0022] In addition, it should be noted that the terms "at least one", "one or more" or similar expressions indicating that a feature or element may exist once or more than once are usually used only once when introducing the respective feature or element. In the following, in most cases, when referring to the respective feature or element, the expression "at least one" or "one or more" will not be repeated, despite the fact that the respective feature or element may exist once or more than once.

[0023] condensation

[0024] The process of the present invention uses 1,3-bis(dimethylaminomethylene)thiourea as a starting material.

[0025] In a preferred embodiment, 1,3-bis(dimethylaminomethylene)thiourea is obtained by condensation of thiourea with dimethylformamide dialkyl acetal, more preferably dimethylformamide dimethyl acetal.

[0026] In a preferred embodiment, the condensation is carried out at a temperature of ≥40°C to ≤70°C, more preferably at a temperature of ≥50°C to ≤65°C.

[0027] In a preferred embodiment, the condensation is carried out in at least one solvent selected from the group consisting of monochlorobenzene, o-dichlorobenzene, nitrobenzene, methylene chloride, ethylene dichloride, chloroform, toluene, o-xylene, m-xylene and p-xylene.

[0028] Step a: Cyclization

[0029] In step a) of the process claimed in the present invention, 1,3-bis(dimethylaminomethylene)thiourea and chloroacetone are reacted to form N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine, wherein chloroacetone is added to the 1,3-bis(dimethylaminomethylene)thiourea suspension at a rate of ≥2.0 vol. % / min to ≤8.0 vol. % / min, based on the total volume of chloroacetone.

[0030] In a preferred embodiment, chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤7.0 vol. % / min, more preferably at a rate of ≥2.0 vol. % / min to ≤6.0 vol. % / min, even more preferably at a rate of ≥3.0 vol. % / min to ≤6.0 vol. % / min, based on the total volume of chloroacetone, for example, a total volume of 650 mL of chloroacetone added over 20 minutes corresponds to 32.5 mL added per minute, which translates into an addition rate of 5.0 vol. % / min based on the total volume of chloroacetone. The specific addition rate allows, on the one hand, to carry out the reaction in a controlled manner when chloroacetone is added rapidly, i.e. to prevent any sharp increase in the temperature of the reaction mixture, and on the other hand, to reduce the amount of impurities when chloroacetone is added slowly.

[0031] In a preferred embodiment, chloroacetone is added as a solution in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, methylene chloride, ethylene dichloride, chloroform, toluene, o-xylene, m-xylene and p-xylene; more preferably, at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, o-xylene, m-xylene and p-xylene; most preferably, at least one solvent is monochlorobenzene.

[0032] In a preferred embodiment, step a) is carried out at a temperature of ≥40°C to ≤75°C, more preferably at a temperature of ≥40°C to ≤70°C.

[0033] In a preferred embodiment, step a) is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, methylene chloride, ethylene dichloride, chloroform, toluene, o-xylene, m-xylene and p-xylene; more preferably, at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, o-xylene, m-xylene and p-xylene; most preferably, the at least one solvent is monochlorobenzene.

[0034] In a preferred embodiment, in step a), the concentration of chloroacetone in at least one solvent is ≥100 g / L to ≤800 g / L, more preferably ≥200 g / L to ≤700 g / L, most preferably ≥400 g / L to ≤600 g / L.

[0035] In a preferred embodiment, in step a), the concentration of 1,3-bis(dimethylaminomethylene)thiourea in at least one solvent is ≥54 g / L to ≤220 g / L.

[0036] In a preferred embodiment, in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is ≧1.20:1.00 to ≦1.01:1.00, more preferably ≧1.10:1.00 to ≦1.01:1.00.

[0037] In another preferred embodiment, step a) is carried out in the absence of any amine, more preferably, step a) is carried out in the absence of any tertiary and secondary amines, even more preferably, in the absence of any amine selected from trimethylamine, triethylamine, methyldiethylamine, tripropylamine, triisopropylamine, diisopropylethylamine, diisopropylamine and dibutylamine.

[0038] Step b: Hydrolysis

[0039] In step b) of the process claimed in the present invention, N′-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine is reacted with at least one acid to form 1-(2-aminothiazol-5-yl)ethanone.

[0040] In a preferred embodiment, in step b), at least one acid is selected from an inorganic acid and an organic acid. Preferably, the inorganic acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, nitric acid, nitrous acid, sulfurous acid, chloric acid, chlorous acid, boric acid and hypochlorous acid. Preferably, the organic acid is selected from lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid and p-toluenesulfonic acid. In a more preferred embodiment, in step b), the at least one acid is hydrochloric acid or sulfuric acid.

[0041] In a preferred embodiment, the pH in step b) is ≥ 1.5 to ≤ 8.0.

[0042] In a preferred embodiment, step b) is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, dichloromethane, dichloroethane, chloroform, toluene, o-xylene, m-xylene and p-xylene; more preferably, at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, o-xylene, m-xylene and p-xylene; most preferably, the at least one solvent is monochlorobenzene.

[0043] In a preferred embodiment, step b) is carried out at a temperature of ≥20°C to ≤110°C, more preferably at a temperature of ≥40°C to ≤90°C, even more preferably at a temperature of ≥50°C to ≤70°C.

[0044] Step c: Sandmeyer reaction

[0045] In step c) of the process claimed in the present invention, 1-(2-aminothiazol-5-yl)ethanone is converted into 1-(2-chlorothiazol-5-yl)ethanone via a Sandmeyer reaction.

[0046] In a preferred embodiment, step c) is carried out in the presence of at least one nitrosating agent and at least one chlorine source, the nitrosating agent is preferably selected from sodium nitrite, potassium nitrite and alkyl nitrite, and the chlorine source is preferably selected from copper (II) chloride, tetraalkylammonium chloride, sodium chloride and hydrochloric acid. In a more preferred embodiment, the at least one nitrosating agent is sodium nitrite, and the at least one chlorine source is sodium chloride and / or hydrochloric acid. In a preferred embodiment, the molar ratio of at least one chlorine source to 1-(2-aminothiazole-5-yl) ethyl ketone is ≥2.0:1.0 to ≤1.0:1.0.

[0047] In a preferred embodiment, step c) is carried out in the presence of at least one catalyst, more preferably the at least one catalyst is selected from copper, copper(I) halides, copper(II) sulfate and copper(II) halides, even more preferably the at least one catalyst is copper(II) sulfate.

[0048] In a preferred embodiment, in step c), the molar ratio of at least one catalyst to 1-(2-aminothiazol-5-yl)ethanone is ≧0.01:1.0 to ≦0.05:1.0.

[0049] In another preferred embodiment, step c) is carried out at a temperature of ≥-10°C to ≤40°C, more preferably at a temperature of ≥-10°C to ≤20°C.

[0050] In a preferred embodiment, step c) is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, dichloromethane, dichloroethane, chloroform, toluene, o-xylene, m-xylene and p-xylene; more preferably, at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, o-xylene, m-xylene and p-xylene; most preferably, the at least one solvent is monochlorobenzene.

[0051] In a preferred embodiment, steps a), b) and c) are carried out in a one-pot reaction, more preferably steps a), b) and c) are carried out in a one-pot reaction using monochlorobenzene as solvent.

[0052] Step d: Chlorination

[0053] In step d) of the process claimed according to the invention, 1-(2-chlorothiazol-5-yl)ethanone is converted into 2-chloro-1-(2-chlorothiazol-5-yl)ethanone via selective chlorination.

[0054] In a preferred embodiment, step d) is carried out in at least one polar solvent selected from sulfoxide, sulfolane, acetonitrile, methylene chloride, ethylene dichloride, monochlorobenzene, o-dichlorobenzene, toluene, dimethyl carbonate, ethylene carbonate, water, acetic acid, formic acid, tetrahydrofuran, 2-methyl-tetrahydrofuran, dimethylformamide, dimethylacetamide, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butyl alcohol, tert-amyl alcohol and ionic liquids, more preferably at least one solvent is acetonitrile. Suitable ionic liquids are selected from 1-alkyl-3-methylimidazolium tetrafluoroborate, 1-alkyl-3-methylimidazolium halide, N-alkylpyridinium tetrafluoroborate and pentafluorophosphate derivatives.

[0055] In a preferred embodiment, step d) is carried out in the presence of at least one chlorinating agent, more preferably at least one chlorinating agent is selected from chlorine, cyanuric chloride, 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, N-chlorophthalimide, sodium dichloroisocyanurate, trimethylsilyl chloride, oxalyl chloride, methanesulfonyl chloride, sulfuryl chloride, acetyl chloride, triethylammonium chloride, alkylimidazolium chloride, sodium chloride and FeCl3.

[0056] In a preferred embodiment, step d) is carried out in the presence of at least one acid catalyst selected from an inorganic acid and an organic acid. Suitable inorganic acids include sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, nitric acid, nitrous acid, sulfurous acid, chloric acid, chlorous acid, boric acid and hypochlorous acid. Suitable organic acids include lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid and p-toluenesulfonic acid.

[0057] In a preferred embodiment, step d) is carried out at a temperature of ≥0°C to ≤40°C, more preferably at a temperature of ≥0°C to ≤20°C.

[0058] advantage

[0059] The claimed invention is associated with at least one of the following advantages:

[0060] (i) The reaction sequence from 1,3-bis(dimethylaminomethylene)thiourea to 1-(2-chlorothiazol-5-yl)ethanone can be carried out in one pot.

[0061] (ii) 1-(2-chlorothiazol-5-yl)ethanone was provided from 1,3-bis(dimethylaminomethylene)thiourea in high overall yield and high purity.

[0062] (iii) 2-Chloro-1-(2-chlorothiazol-5-yl)ethanone was provided from 1,3-bis(dimethylaminomethylene)thiourea in high overall yield and high selectivity.

[0063] (iv) The method of the present invention uses a solvent that is mild in process.

[0064] (v) The process of the present invention involves low effluent loading and low metal loading.

[0065] (vi) The method of the present invention is safe and can be easily controlled.

[0066] (vii) The process of the present invention is economical because chloroacetone is added within a reasonable process time.

[0067] Below, a list of embodiments is provided to further illustrate the present disclosure without intending to limit the present disclosure to the specific embodiments listed below.

[0068] Implementation plan:

[0069] 1. A method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, comprising at least the following steps:

[0070] a) cyclizing 1,3-bis(dimethylaminomethylene)thiourea with chloroacetone to form N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine,

[0071] b) subjecting (5-acetylthiazol-2-yl)-N,N-dimethylformamidine to at least one acid to form 1-(2-aminothiazol-5-yl)ethanone,

[0072] c) subjecting 1-(2-aminothiazol-5-yl)ethanone to a Sandmeyer reaction to form 1-(2-chlorothiazol-5-yl)ethanone, and

[0073] d) chlorinating 1-(2-chlorothiazol-5-yl)ethanone to form 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, wherein in step a) chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤8.0 vol. % / min, based on the total volume of chloroacetone.

[0074] 2. The method according to embodiment 1, wherein in step a), chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤7.0 vol. % / min, based on the total volume of chloroacetone.

[0075] 3. The method according to embodiment 1, wherein 1,3-bis(dimethylaminomethylene)thiourea is obtained by condensation of thiourea with dimethylformamide dialkyl acetal.

[0076] 4. The method according to embodiment 3, wherein the condensation is carried out at a temperature of ≥40°C to ≤70°C.

[0077] 5. The method according to embodiment 3 or 4, wherein the condensation is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, dichloromethane, dichloroethane, chloroform, toluene, o-xylene, m-xylene and p-xylene.

[0078] 6. The method according to any one of embodiments 1-5, wherein step a) is carried out at a temperature of ≥40°C to ≤75°C.

[0079] 7. The method according to any one of embodiments 1 to 6, wherein step a) is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, dichloromethane, dichloroethane, chloroform, toluene, o-xylene, m-xylene and p-xylene.

[0080] 8. The method according to embodiment 7, wherein in step a), the concentration of chloroacetone in at least one solvent is ≥100 g / L to ≤800 g / L.

[0081] 9. The method according to any one of embodiments 1-8, wherein in step a), the concentration of 1,3-bis(dimethylaminomethylene)thiourea in at least one solvent is ≥54 g / L to ≤220 g / L.

[0082] 10. The method according to any one of embodiments 1-9, wherein in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is ≥1.20:1.00 to ≤1.01:1.00.

[0083] 11. The process according to any one of embodiments 1-10, wherein step a) is performed in the absence of any amine.

[0084] 12. The method according to any one of embodiments 1 to 11, wherein in step b), at least one acid is selected from inorganic acids and organic acids.

[0085] 13. The method of embodiment 12, wherein the inorganic acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, nitric acid, nitrous acid, sulfurous acid, chloric acid, chlorous acid, boric acid and hypochlorous acid.

[0086] 14. The method according to embodiment 12, wherein the organic acid is selected from lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid and p-toluenesulfonic acid.

[0087] 15. The method according to embodiment 12, wherein in step b), the at least one acid is hydrochloric acid or sulfuric acid.

[0088] 16. The method according to any one of embodiments 1-15, wherein in step b) the pH is ≥ 1.5 to ≤ 8.0.

[0089] 17. The method according to any one of embodiments 1 to 16, wherein step b) is carried out in at least one solvent selected from monochlorobenzene, o-dichlorobenzene, nitrobenzene, dichloromethane, dichloroethane, chloroform, toluene, o-xylene, m-xylene and p-xylene.

[0090] 18. The process according to any one of embodiments 1-17, wherein step b) is carried out at a temperature of ≥20°C to ≤110°C.

[0091] 19. The method according to any one of embodiments 1-18, wherein step c) is performed in the presence of at least one nitrosating agent and at least one chlorine source.

[0092] 20. The method according to embodiment 19, wherein the at least one nitrosating agent is selected from sodium nitrite, potassium nitrite and alkyl nitrite.

[0093] 21. The method of embodiment 19, wherein at least one chlorine source is selected from copper (II) chloride, tetraalkylammonium chloride, sodium chloride and hydrochloric acid.

[0094] 22. The method of any one of embodiments 19-21, wherein the molar ratio of at least one chlorine source to 1-(2-aminothiazol-5-yl)ethanone is ≥2.0:1.0 to ≤1.0:1.0.

[0095] 23. The method according to any one of embodiments 1-22, wherein step c) is performed in the presence of at least one catalyst.

[0096] 24. The method according to embodiment 23, wherein the at least one catalyst is selected from copper, copper (I) halide, copper (II) sulfate and copper (II) halide.

[0097] 25. The method according to embodiment 23 or 24, wherein in step c), the molar ratio of at least one catalyst to 1-(2-aminothiazol-5-yl)ethanone is ≥0.01:1.0 to ≤0.05:1.0.

[0098] 26. The process according to any one of embodiments 1-25, wherein step c) is carried out at a temperature of ≥ -10°C to ≤ 40°C.

[0099] 29. The method according to any one of embodiments 1 to 26, wherein step d) is carried out in at least one polar solvent selected from sulfoxide, sulfolane, acetonitrile, dichloromethane, dichloroethane, monochlorobenzene, o-dichlorobenzene, dimethyl carbonate, ethylene carbonate and ionic liquids.

[0100] 28. The process according to any one of embodiments 1-27, wherein step d) is carried out in the presence of at least one chlorinating agent.

[0101] 29. The method of embodiment 28, wherein the at least one chlorinating agent is selected from chlorine, cyanuric chloride, 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, N-chlorophthalimide, sodium dichloroisocyanurate, trimethylsilyl chloride, oxalyl chloride, methanesulfonyl chloride, sulfuryl chloride, acetyl chloride, triethylammonium chloride, alkylimidazolium chloride, sodium chloride and FeCl3.

[0102] 30. The process according to any one of embodiments 1-29, wherein step d) is performed at a temperature of ≥0°C to ≤40°C.

[0103] 31. The method according to any one of embodiments 1-30, wherein steps a), b) and c) are performed in a one-pot reaction. Example

[0104] The invention is illustrated in detail by the following non-limiting working examples.

[0105] method

[0106] Characterization was performed by coupled high performance liquid chromatography / mass spectrometry (HPLC / MS), gas chromatography (GC), NMR or melting point.

[0107] HPLC method: Agilent Eclipse Plus C18, 150 mm × 4.6 mm ID × 5 μm

[0108] Gradient A = 0.1% TFA in water, B = 0.1% TFA in acetonitrile.

[0109] Flow rate = 1.4 mL / min, column furnace temperature = 30 °C

[0110] Gradient program = 10% B-100% B-5 min, hold 2 min, 3 min-10% B.

[0111] Run time = 10 min LCMS method 1: C18 column (50 mm x 3.0 mm x 3 μm)

[0112] Gradient A = 10 mM aqueous ammonium formate, B = 0.1% formic acid in acetonitrile

[0113] Flow rate = 1.2 mL / min, column furnace temperature = 40 °C

[0114] Gradient program = 10% B to 100% B in 1.5 min, hold 100% B for 1 min, 1 min - 10% B

[0115] Run time: 3.75min

[0116] 1 H-NMR: The signals are characterized by the chemical shift (ppm) relative to tetramethylsilane, their multiplicity and their integration (relative number of given hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signals: m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

[0117] Abbreviations used are: h for hours, min for minutes, rt for retention time and ambient temperature for 20-25°C.

[0118] Example 1

[0119] Preparation of (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea

[0120]

[0121] Under nitrogen atmosphere, thiourea (500 g), monochlorobenzene (MCB) (5 L) and dimethylformamide dimethyl acetal (2.19 L) were added to a 16 L reactor. The reaction mass was stirred at 55-60 ° C for 3 hours. After 3 hours, 2.5 L of solvent (methanol and MCB) was distilled under vacuum to obtain (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea as a suspension in MCB. The suspension was used as is in step b. [99% of theoretical yield, m / z=187 amu (M+H + )],HPLC RT:4.70

[0122] 1 H NMR (300 MHz, CDCl3): 3.17 (s, 6H), 3.20 (s, 6H), 8.92 (s, 2H). Step a: Preparation of N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine

[0123]

[0124] In a 16 L reactor, MCB (2 L) was added to a suspension of (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea in MCB. The reactor jacket was set to 45°C and a solution of chloroacetone (0.65 L) in MCB (0.5 liter) was metered in over 20 minutes under a nitrogen atmosphere (an exotherm of 25-30°C was observed during the addition of chloroacetone). After complete addition of chloroacetone, the reaction mass was brought to 55-60°C and stirred for 0.5 hours. HPLC observed >99% conversion to N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine. The reaction mass was carried on to the next step as is in the same reactor. [99% of theoretical yield, m / z=198 amu (M+H + )]. HPLC RT:6.05, 1 H NMR (300 MHz, CDCl3): 2.28 (s, 3H), 3.10 (s, 3H), 3.12 (s, 3H), 7.93 (s, 1H), 8.28 (s, 1H). Step b: Preparation of 1-(2-aminothiazol-5-yl)ethanone

[0125]

[0126] To the above reaction mass was added aqueous HCl (35%, 2.5 L) at 55-60°C over 25 minutes (an exotherm of 5°C was observed). Demineralized water (0.5 L) was added at 55-60°C and stirred for 2 hours. After 2 hours, HPLC showed >99% conversion to the desired product. The agitator was stopped and aqueous phase 1 was separated at 55-60°C. Aqueous HCl (35%, 1 L) was added to the organic phase and the two-phase mixture was stirred at the same temperature for 15-20 minutes. Aqueous phase 2 was separated again and combined with aqueous phase 1. The combined aqueous phase was used as is in the next step in the same reactor. [99% of theoretical yield, m / z=143 amu (M+H + )]. HPLC RT:4.49, 1 HNMR (300MHz, DMSO 6 ):2.34(s,3H),7.91(s,1H),7.99(brs,2H).

[0127] Step c: Preparation of 1-(2-chlorothiazol-5-yl)ethanone

[0128]

[0129] To the aqueous solution of step b was added aqueous HCl (35%, 1 L) and the solution was cooled to -7°C. CuSO4·5H2O (0.16 kg) and NaCl (0.35 kg) were added. A solution of NaNO2 (0.94 kg) in water (1.2 L) was added between -7 and 3°C over a period of 2.5 hours. After complete addition, the reactants were stirred at 10-15°C for 0.5 hours. MCB (2 L) and water (2 L) were added and stirred for 10 minutes. The aqueous phase was separated and extracted with MCB (1 L). The combined organic phases were washed with saturated aqueous NaHCO3 (1 L) and water (1 L). The organic phase was separated and MCB was distilled under vacuum to give 1-(2-chlorothiazol-5-yl)ethanone (1.02 kg). [85% of the theoretical yield over 4 steps. GCMS, m / z=161 amu.] HPLC RT: 6.94, 1 H NMR (300MHz, CDCl3): 2.58 (s, 3H), 8.08 (s, 1H).

[0130] Step d: Preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone

[0131]

[0132] Under nitrogen atmosphere, 1-(2-chlorothiazol-5-yl)ethanone (150 g) and acetonitrile (330 mL) were added to a 2L 3-necked flask equipped with a Teflon blade stirrer, an addition funnel, and a heat bag, and cooled to 15-20°C. Sulfuryl chloride (73 mL) was added dropwise at 15-20°C over 0.5 hours. The reaction mass was heated to ambient temperature and stirred for 5 hours. The weak HCl salt of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone precipitated from the reaction; the suspension was cooled to 0-5°C and stirred for 10 minutes. The precipitate was washed with cold acetonitrile (25 mL). The solid was dried under vacuum at 35°C. The weak HCl salt decomposed during the drying process to give a beige solid 2-chloro-1-(2-chlorothiazol-5-yl)ethanone [80% of theoretical yield, m / z=195 amu (M+H + )]. HPLC RT:7.90. 1 H NMR (300MHz, CDCl3): 4.52 (s, 2H), 8.21 (s, 1H).

[0133] Example 2

[0134] Preparation of (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea

[0135] Under nitrogen atmosphere, thiourea (70 g), monochlorobenzene (MCB) (955 ml) and dimethylformamide dimethyl acetal (294 ml) were added to a 1.6 L reactor. The reaction mass was stirred at 55-60 ° C for 3 hours. After 3 hours, 385 ml of solvent (methanol and MCB) was distilled under vacuum to obtain (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea as a suspension in MCB. The suspension was used as is in step b. [99% of theoretical yield, m / z=187 amu (M+H + )],HPLC RT:4.70

[0136] 1 H NMR (300 MHz, CDCl3): 3.17 (s, 6H), 3.20 (s, 6H), 8.92 (s, 2H). Step a: Preparation of N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine

[0137] In a 1.6 L reactor, a suspension of (1,3E / Z)-1,3-bis(dimethylaminomethylene)thiourea in MCB was added. The reactor jacket was set to 55°C, a vacuum of 200-250 mbar was applied, and a solution of chloroacetone (86.8 ml) in MCB (70 ml) was metered in over 2-3 hours using a dip tube (an exotherm of 3-5°C was observed during the addition of chloroacetone). After complete addition of chloroacetone, the reaction mass was stirred at 60°C for 0.5 hours. HPLC observed >99% conversion to N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine. The reaction mass was carried out as is in the same reactor for the next step. [97% of theoretical yield, m / z=198 amu (M+H + )]. HPLC RT:6.05, 1 H NMR (300 MHz, CDCl3): 2.28 (s, 3H), 3.10 (s, 3H), 3.12 (s, 3H), 7.93 (s, 1H), 8.28 (s, 1H). Step b: Preparation of 1-(2-aminothiazol-5-yl)ethanone

[0138] To the above reaction mass was added aqueous HCl (35%, 407 ml) at 55-60°C over 40 minutes (5°C exotherm observed). Demineralized water (70 ml) was added at 55-60°C and stirred for 2 hours. After 2 hours, HPLC showed >99% conversion to the desired product. The agitator was stopped and aqueous phase 1 was separated at 55-60°C. Aqueous HCl (35%, 166 ml) was added to the organic phase and the two-phase mixture was stirred at the same temperature for 15-20 minutes. Aqueous phase 2 was separated again and combined with aqueous phase 1. The combined aqueous phase was used as is in the next step in the same reactor. [98% of theoretical yield, m / z=143 amu (M+H + )]. HPLCRT:4.49, 1 H NMR (300 MHz, DMSO 6 ):2.34(s,3H),7.91(s,1H),7.99(brs,2H).

[0139] Step d: Preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone

[0140] Method-1:

[0141] In a 1 L jacketed reactor equipped with a glass blade stirrer and a heat bag under nitrogen atmosphere, a 55.5 wt% solution of 1-(2-chlorothiazol-5-yl)ethanone in monochlorobenzene (180 g) was added, the flask was rinsed with monochlorobenzene (72 ml) and acetonitrile (300 mL) and cooled to 15-20°C. Chlorine gas (90 gm) was purged at 15-20°C for 2-3 hours. The reaction mass was stirred at 15-20°C for 3 hours. The weak HCl salt of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone precipitated from the reaction. Monochlorobenzene (200 ml) was added and the suspension was refluxed for 40 minutes. The solvent (MCB:CAN, 226 ml) was evaporated. To the residual water (102 ml) was added, followed by 5% NaHCO3 (90 ml). The organic phase was separated and washed with water (100 ml) again. The organic phase was evaporated in vacuo to give 2-chloro-1-(2-chlorothiazol-5-yl)ethanone as a 24% solution in MCB [80% of theoretical yield, m / z = 195 amu (M+H + )]. HPLC RT:7.90. 1 H NMR (300MHz, CDCl3): 4.52 (s, 2H), 8.21 (s, 1H).

[0142] Method-2:

[0143] 1-(2-chlorothiazol-5-yl)ethanone (92 g), toluene (92 g) and acetonitrile (368 g) were added to a 1 L jacketed reactor equipped with a glass blade stirrer and a heat bag. Under nitrogen atmosphere, room temperature. Chlorine (45 gm) was purged at 25-30°C for 2-3 hours. The reaction mass was stirred at room temperature for 3 hours. The reaction mass was cooled to 0-5°C and stirred for 30 minutes. The solid 2-chloro-1-(2-chlorothiazol-5-yl)ethanone precipitated from the solution was filtered and dried under vacuum. [73% of theoretical yield, m / z=195 amu (M+H + )]. HPLC RT:7.90. 1 H NMR (300MHz, CDCl3): 4.52 (s, 2H), 8.21 (s, 1H).

[0144] Crystallization of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone:

[0145] The crude material (571 g, 84.52%) was dissolved in IPA (856 ml) and heated at 60° C. to give a clear solution, stirred for 30 minutes, gradually cooled to 0° C., and stirred for 30 minutes. The solid was filtered and vacuum dried to give 2-chloro-1-(2-chlorothiazol-5-yl)ethanone (443 g, 98.9 wt %, 92% of theoretical yield) as a beige solid.

[0146] It was found that the rate of addition of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is critical. On the one hand, if the chloroacetone is added too quickly, the reaction is no longer controllable and exceeds a temperature of 70°C. On the other hand, if the chloroacetone is added too slowly, the yield of 1,3-bis(dimethylaminomethylene)thiourea decreases and other by-products are formed, which negatively affect the overall yield of the synthesis of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone.

[0147] Table 1 below gives an overview of the different addition rates. All examples were carried out according to Example 1a. However, in each case, the addition rate of chloroacetone was changed. Unknown impurities and reverse impurities N,N-dimethyl-N'-(4-methylthiazol-2-yl)formamidine were detected.

[0148] Table 1

[0149]

[0150] *Not within the scope of this invention

Claims

1. A method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, comprising at least the following steps: a) cyclizing 1,3-bis(dimethylaminomethylene)thiourea with chloroacetone to form N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine, b) subjecting N'-(5-acetylthiazol-2-yl)-N,N-dimethylformamidine to at least one acid to form 1-(2-aminothiazol-5-yl)ethanone, c) subjecting 1-(2-aminothiazol-5-yl)ethanone to a Sandmeyer reaction to form 1-(2-chlorothiazol-5-yl)ethanone, and d) chlorinating 1-(2-chlorothiazol-5-yl)ethanone to form 2-chloro-1-(2-chlorothiazol-5-yl)ethanone, wherein in step a) chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤8.0 vol. % / min, based on the total volume of chloroacetone.

2. The process according to claim 1, wherein in step a), chloroacetone is added at a rate of ≥2.0 vol. % / min to ≤7.0 vol. % / min, based on the total volume of chloroacetone.

3. The method according to claim 1, wherein step a) is carried out at a temperature of ≥40°C to ≤75°C.

4. The method according to claim 2, wherein step a) is carried out at a temperature of ≥40°C to ≤75°C.

5. The method according to claim 1, wherein in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is 1.20:1.00 to 1.01:1.

00.

6. The method according to claim 2, wherein in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is 1.20:1.00 to 1.01:1.

00.

7. The method according to claim 3, wherein in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is 1.20:1.00 to 1.01:1.

00.

8. The method according to claim 4, wherein in step a), the molar ratio of chloroacetone to 1,3-bis(dimethylaminomethylene)thiourea is 1.20:1.00 to 1.01:1.

00.

9. The process according to any one of claims 1 to 8, wherein step a) is carried out in the absence of any amine.

10. The process according to any one of claims 1 to 8, wherein in step b), at least one acid is selected from inorganic acids and organic acids.

11. The method according to claim 9, wherein in step b), at least one acid is selected from inorganic acids and organic acids.

12. The process according to any one of claims 1 to 8, wherein step b) is carried out at a temperature of ≥20°C to ≤110°C.

13. The process according to claim 11, wherein step b) is carried out at a temperature of ≥20°C to ≤110°C.

14. The process according to any one of claims 1 to 8, wherein step c) is carried out in the presence of at least one nitrosating agent and at least one chlorine source.

15. The process according to claim 13, wherein step c) is carried out in the presence of at least one nitrosating agent and at least one chlorine source.

16. The process according to any one of claims 1 to 8, wherein step c) is carried out in the presence of at least one catalyst.

17. The process according to claim 15, wherein step c) is performed in the presence of at least one catalyst.

18. The process according to any one of claims 1 to 8, wherein step c) is performed at a temperature of ≥ -10°C to ≤ 40°C.

19. The method according to claim 17, wherein step c) is carried out at a temperature of ≥ -10°C to ≤ 40°C.

20. The process according to any one of claims 1 to 8, wherein step d) is carried out in the presence of at least one chlorinating agent.

21. The process of claim 19, wherein step d) is performed in the presence of at least one chlorinating agent.

22. The process according to any one of claims 1 to 8, wherein step d) is performed at a temperature of ≥ 0°C to ≤ 40°C.

23. The process according to claim 21, wherein step d) is carried out at a temperature of ≥0°C to ≤40°C.

24. The process according to any one of claims 1 to 8, wherein steps a), b) and c) are performed in a one-pot reaction.

25. The method of claim 23, wherein steps a), b) and c) are performed in a one-pot reaction.

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