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

Abstract

The present invention relates to a process for the preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone.

Description

Field of the invention

[0001] The present invention relates to a process for the preparation of 2-chloro-1-(2- chlorothiazol-5-yl)ethanone. BACKGROUND

[0003] 2-chloro-1-(2-chlorothiazol-5-yl)ethanone is a pyridine compound whose synthesis is of interest. These compounds exhibit excellent insecticidal properties.

[0004] WO 2018 / 197541 A1 and WO2018 / 202654 A1 disclose synthesis routes of these pyridine compounds which include the reaction of chloro-(2-chlorothiazol-5-yl)magnesium species and 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, FimH antagonists 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 processes of the prior art have several drawbacks such as high effluent load and metal salt load, low yield, low selectivity and use of toxic solvents.

[0007] It was therefore an object of the present invention to provide a process for the preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone which provides 2-chloro-1-(2-chlorothiazol-5- yl)ethanone in high overall yield, i.e. in an overall yield of > 80% or > 75% or > 70% and in high selectivity.

[0008] Therefore, efforts have been made to find an improved batch reaction procedure and an alternative process which offers advantages compared to the classical batch synthesis procedure for the synthesis of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone. SUMMARY

[0010] It has surprisingly been found that the reaction of 2-chlorothiazole with alkylmagnesium halide and the subsequent reaction of this product with chloroacetyl chloride leads to the formation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone in high yield and high selectivity within reasonable process times.

[0011] A process for the preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone comprises at least the following steps:

[0012] a) preparing a compound of formula I by reaction of 2-chlorothiazole with RMgX wherein R is C1-C6 alkyl

[0013]

[0014] wherein X is halogen;

[0015] b1 ) adding the compound of formula (I) to chloroacetyl chloride in a batch reactor;

[0016] or

[0017] b2) reacting the compound of formula (I) with chloroacetyl chloride in a continuous flow reactor. DETAILED DESCRIPTION

[0019] Before the present compositions, formulations, and conditions are described, it is to be understood that this application is not limited to the particular compositions, formulations, and conditions described, as such compositions, formulations, and conditions may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present application will be limited only by the appended claims.

[0020] The skilled person is familiar with batch synthesis in a batch reactor and continuous flow synthesis in a continuous flow reactor, which methods or reactors are known in the art.

[0021] If hereinafter a group is defined to comprise at least a certain number of embodiments, this is intended to also cover preferred groups, which consist only of those embodiments. Furthermore, the terms "first", "second", "third" or "a", "b", "c", and the like, used in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and are merely used to differentiate one element from another. It is to be understood that the embodiments of the present application described herein including the preferred embodiments can be operated in other sequences than the one described herein or illustrated in the examples. In case the terms "first", "second", "third" or "(A)", "(B)", and "(C)", or "(a)", "(b)", "(c)", "(d)", "i", "ii", etc. relate to steps of a method or use or detection, there is no time or time interval coherence between the steps, that is, the steps can be carried out simultaneously or there can be time intervals of seconds, minutes, hours, days, weeks, months or even years between the steps, unless otherwise indicated in the application as set forth herein above or below.

[0022] Furthermore, the ranges of values that are set forth in this specification are intended to be inclusive of the endpoints, e.g., the range from 1 to 10 is intended to include 1 and 10. For an overage of doubt, Applicants have the right to amend the claims to expressly recite these limits. Any open-ended claim such as to "comprise," "having," "including," "containing," "characterized by," "including the features of," "having the features of," "containing the features of," etc. should be interpreted to leave open the possibility that the recited element or feature can be added to the claimed invention.

[0023] In the following passages, different aspects of the application are defined in more detail. Each aspect so defined can be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous.

[0024] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the application. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but can refer to different embodiments. Furthermore, the terms "preferably," "more preferably," "even more preferably," "most preferably," and "especially" used throughout this application, are used to describe a preference for, but do not pose a substantive limit on, the various embodiments of the application. Thus, an element or characteristic that is introduced by such a term is an optional element and is not intended to limit the scope of the claims in any way.

[0025] Furthermore, the particular elements, structures, or characteristics can be combined in any suitable manner in one or more embodiments. It will also be appreciated by those of skill in the art that one or more embodiments of the application can include other elements, structures, or characteristics not expressly mentioned herein. Additionally, although some embodiments described herein comprise one or more elements, features, or characteristics, embodiments of the application can also comprise other elements, features, or characteristics not expressly mentioned herein. For example, in the claims, any of the claimed embodiments can be used in any combination.

[0026] The term "alkyl" as used herein and in the alkyl moiety of alkoxy, alkylthio, and the like, refers to a saturated straight or branched chain hydrocarbon group having from 1 to 2 ("Ci-C2alkyl"), 1 to 3 ("Ci-C3alkyl"), 1 to 4 ("Ci-C4alkyl"), or 1 to 6 ("Ci-C6alkyl") carbon atoms. Ci-C2alkyl is CH3or C2H5. Ci-C3alkyl is additionally propyl and isopropyl. Ci-C4alkyl is additionally butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), or 1,1-dimethylethyl (tert-butyl). Ci-C6alkyl is still additionally, for example, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0027] Furthermore, it should be pointed out that the term "at least one", "one or more" or similar wording indicating that a certain feature or element can exist once or more than once is typically used only once when introducing the respective feature or element. Subsequently, in most cases, when referring to the respective feature or element, the wording "at least one" or "one or more" is not repeated, even though in fact the respective feature or element can exist once or more than once.

[0028] The process of the present application uses a compound of formula I as starting material.

[0029]

[0030] wherein X is halogen;

[0031] Step a):

[0032] In one embodiment, the compound of formula I is obtained by reaction of 2-chlorothiazole with RMgX, wherein R is Ci-C6alkyl.

[0033] In a preferred embodiment, R is isopropyl;

[0034] In a preferred embodiment, X is Cl;

[0035] In a preferred embodiment, RMgX is isopropylmagnesium chloride;

[0036] In a preferred embodiment, RMgX and 2-chlorothiazole are used in a molar ratio in the range of > 0.9 : 1.00 to < 1.3 : 1.00, more preferably in the range of > 1.00 : 1.00 to < 1.1 : 1.00.

[0037] In a preferred embodiment, the reaction is carried out in at least one solvent selected from the group consisting of tetrahydrofuran, dimethoxyethane and mixtures thereof.

[0038] In a preferred embodiment, the reaction is carried out by adding a tetrahydrofuran solution of isopropylmagnesium chloride to a dimethoxyethane solution of 2-chlorothiazole.

[0039] In a preferred embodiment, the initial concentration of 2-chlorothiazole in dimethoxyethane is in the range of > 119 g / L to < 790 g / L, more preferably in the range of > 198 g / L to < 474 g / L, most preferably in the range of > 198 g / L to < 474 g / L.

[0040] In a preferred embodiment, isopropylmagnesium chloride is used as a solution in tetrahydrofuran, more preferably as a 20 wt.-% solution in tetrahydrofuran.

[0041] In a preferred embodiment, the reaction is carried out at a temperature in the range of > -20 °C to < 40 °C, more preferably in the range of > 0 °C to < 10 °C.

[0042] In a preferred embodiment, the rate of addition of isopropylmagnesium chloride is such that the reaction temperature is maintained in the range of > -20 °C to < 40 °C, more preferably in the range of > 0 °C to < 10 °C.

[0043] In one embodiment of the present application, step a) is followed by step b1).

[0044] Step b1): reacting the compound of formula (I) with chloroacetyl chloride in a batch reactor;

[0045] In step b1) of the process according to the present application, the compound of formula I and chloroacetyl chloride are reacted to form 2-chloro-1-(2-chlorothiazol-5-yl)ethanone.

[0046] In a preferred embodiment, in step b1) chloroacetyl chloride and the compound of formula (I) are used in a molar ratio in the range of > 1.00 : 1.00 to < 5.00 : 1.00, more preferably in the range of > 2.00 : 1.00 to < 3.5 : 1.00, most preferably the molar ratio of chloroacetyl chloride to the compound of formula I is 3.00 : 1.00.

[0047] In a preferred embodiment, step b1 ) is carried out in at least one solvent selected from toluene, tetrahydrofuran, dimethoxyethane and mixtures thereof.

[0048] In a preferred embodiment, the chloroacetyl chloride is used as a solution in toluene.

[0049] In a preferred embodiment, the initial concentration of chloroacetyl chloride in toluene is in the range of > 119 g / L to < 790 g / L, more preferably in the range of > 198 g / L to < 474 g / L, most preferably in the range of > 198 g / L to < 474 g / L.

[0050] In a preferred embodiment, the chloroacetyl chloride is added to the solution of the compound of formula I of step a).

[0051] In another preferred embodiment, the solution of the compound of formula I of step a) is added to the chloroacetyl chloride.

[0052] In an embodiment, step b1 ) is carried out at a temperature of > -70 °C to < -35 °C, preferably at a temperature of > -60 °C to < -40 °C, more preferably at a temperature of > -52 °C to < -48 °C, most preferably at a temperature of -50 °C.

[0053] In a preferred embodiment, the rate at which the compound of formula I is added to the chloroacetyl chloride in step b1 ) is such that the reaction temperature is maintained in the range of > -70 °C to < -35 °C, preferably at a temperature of > -60 °C to < -40 °C, more preferably at a temperature of > -52 °C to < -48 °C, most preferably at a temperature of -50 °C.

[0054] In another preferred embodiment, the rate at which the chloroacetyl chloride is added to the solution of the compound of formula I of step a) is such that the reaction temperature is maintained in the range of > -70 °C to < -35 °C, preferably at a temperature of > -60 °C to < -40 °C, more preferably at a temperature of > -52 °C to < -48 °C, most preferably at a temperature of -50 °C.

[0055] In another embodiment of the present application, step b2) follows step a).

[0056] Step b2): reacting the compound of formula (I) with chloroacetyl chloride in a continuous flow reactor.

[0057] In step b2) of the process according to the present application, the reaction is carried out by continuously feeding the compound of formula I and chloroacetyl chloride into a continuous flow reactor;

[0058] In one embodiment, step b2) is carried out at a temperature of > -50 °C to < +50 °C, preferably at a temperature of > -40 °C to < +20 °C, more preferably at a temperature of +0 °C;

[0059] In one preferred embodiment, in step b2) the chloroacetyl chloride and the compound of formula (I) are used in a molar ratio in the range of > 1.00 : 1.00 to < 5.00 : 1.00, more preferably in the range of > 2.00 : 1.00 to < 3.5 : 1.00, most preferably the molar ratio of chloroacetyl chloride to compound of formula I is 1.00 : 1.00;

[0060] In one preferred embodiment, step b2) is carried out in at least one solvent selected from the group consisting of toluene, tetrahydrofuran, dimethoxyethane and mixtures thereof;

[0061] In a more preferred embodiment, step b2) is carried out in the solvent tetrahydrofuran.

[0062] In one preferred embodiment, in step b2) the continuous flow reactor is selected from the group consisting of a tubular reactor, a loop reactor and a continuous oscillating reactor, which are capable of achieving high heat transfer rates;

[0063] The mixing of the compound of formula I and the chloroacetyl chloride can be carried out with any passive or active mixer. Due to the mixing in step b2) a homogeneous reaction medium can be obtained before the reaction starts. Thus, concentration gradients can be less, leading to a better selectivity. Due to the heat transfer, the heat of this exothermic reaction can be quickly removed. Thus, hot spots leading to side components can be minimized.

[0064] In one preferred embodiment, in step b2) the surface of the inner walls of the continuous flow reactor is made of stainless steel or Hastelloy.

[0065] Advantages

[0066] The present application is associated with at least one of the following advantages:

[0067] (i) Step a) and the subsequent step b1) can be carried out in one pot.

[0068] (ii) Step b2) can be reacted in a continuous flow reactor, wherein the reaction is carried out in a short time, thus forming less side products.

[0069] (iii) 2-Chloro-1-(2-chlorothiazol-5-yl)ethanone is provided from 2-chlorothiazole in high overall yield and high purity.

[0070] (iv) 2-Chloro-1-(2-chlorothiazol-5-yl)ethanone is provided from 2-chlorothiazole in high overall yield and high selectivity

[0071] (v) The process of the present application can use a process friendly solvent.

[0072] (vi) The process of the present application can involve a low effluent load.

[0073] (vii) The process of the present application is safe and easy to control.

[0074] (viii) The process of the present application is economical as the compound of formula I is added within a reasonable process time.

[0075] A series of embodiments are provided below to further illustrate the present disclosure without intending to limit the present disclosure to the specific embodiments listed below.

[0076] Embodiments:

[0077] 1. A process for the preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ethanone comprising at least the following steps:

[0078] a) preparing a compound of formula I by reaction of 2-chlorothiazole with RMgX wherein R is Ci-C6-alkyl

[0079]

[0080] wherein X is halogen;

[0081] b1) reacting the compound of formula (I) with chloroacetyl chloride in a batch reactor;

[0082] or

[0083] b2) reacting the compound of formula (I) with chloroacetyl chloride in a continuous flow reactor.

[0084] 2. The process according to embodiment 1, wherein in step a) R is isopropyl.

[0085] 3. The process according to embodiment 1 or 2, wherein in step a) X is CI.

[0086] 4. The process according to any one of embodiment 1, wherein in step a) RMgX is isopropylmagnesium chloride.

[0087] 5. The process according to any one of embodiments 1 to 4, wherein in step a) RMgX and 2-chlorothiazole are used in a molar ratio in the range of > 0.9 : 1.00 to < 1.3 : 1.00.

[0088] 6. The process according to any one of embodiments 1 to 5, wherein in step a) isopropylmagnesium chloride and 2-chlorothiazole are used in a molar ratio in the range of > 1.00 : 1.00 to < 1.1 : 1.00.

[0089] 7. The process according to any one of embodiments 1 to 6, wherein the reaction in step a) is carried out in at least one solvent selected from tetrahydrofuran, dimethoxyethane and mixtures thereof.

[0090] 8. The process according to any one of embodiments 1 to 6, wherein in step a) 2-chlorothiazole is used as a solution in dimethoxyethane.

[0091] 9. The process according to any one of embodiment 8, wherein the concentration of 2-chlorothiazole in dimethoxyethane in step a) is in the range of > 119 g / L to < 790 g / L.

[0092] 10. The process according to embodiment 8 or 9, wherein the concentration of 2-chlorothiazole in dimethoxyethane in step a) is in the range of > 198 g / L to < 474 g / L.

[0093] 11. The process according to embodiment 7, wherein the concentration of 2-chlorothiazole in at least one solvent in step a) is in the range of > 100 g / L to < 800 g / L.

[0094] 12. The process according to any one of embodiments 8 to 11, wherein the concentration of 2-chlorothiazole in dimethoxyethane in step a) is 395 g / L.

[0095] 13. The process according to any one of embodiments 1 to 12, wherein the reaction in step a) is carried out at a temperature in the range of > -20 °C to < 40 °C.

[0096] 14. The process according to any one of embodiments 1 to 13, wherein the reaction in step a) is carried out at a temperature in the range of > 0 °C to < 10 °C.

[0097] 15. The process according to embodiment 1, wherein step b1) is subsequent to step a).

[0098] 16. The process according to embodiment 1 or 15, wherein the molar ratio of chloroacetyl chloride to the compound of formula I in step b1) is in the range of > 1.00 : 1.00 to < 5.00 : 1.00.

[0099] 17. The process according to any one of embodiments 1, 15 or 16, wherein the molar ratio of chloroacetyl chloride to the compound of formula I in step b1) is in the range of > 2.00 : 1.00 to < 3.5 : 1.00.

[0100] 18. The process according to any one of embodiments 1 and 15 to 17, wherein step b1) is carried out in at least one solvent selected from toluene, tetrahydrofuran, dimethoxyethane and mixtures thereof.

[0101] 19. The process according to embodiments 1 and 15 to 18, wherein in step b1 ) chloroacetyl chloride is used as a solution in toluene.

[0102] 20. The process according to embodiments 1 and 15 to 19, wherein the concentration of chloroacetyl chloride in toluene in step b1 ) is in the range of > 119 g / L to < 790 g / L.

[0103] 21. The process according to embodiments 1 and 15 to 20, wherein the concentration of chloroacetyl chloride in toluene in step b1 ) is in the range of > 198 g / L to < 474 g / L.

[0104] 22. The process according to any one of embodiments 1 and 15 to 21, wherein the concentration of chloroacetyl chloride in toluene in step b1 ) is 395 g / L.

[0105] 23. The process according to any one of embodiments 1 and 15 to 22, wherein step b1 ) is carried out at a temperature of > -70 °C to < -35 °C.

[0106] 24. The process according to any one of embodiments 1 and 15 to 23, wherein step b1 ) is carried out at a temperature of > -60 °C to < -40 °C.

[0107] 25. The process according to any one of embodiments 1 and 15 to 24, wherein step b1 ) is carried out at a temperature of > -55 °C to < -45 °C.

[0108] 26. The process according to any one of embodiments 1 and 15 to 25, wherein step b1 ) is carried out at a temperature of -50 °C.

[0109] 27. The process according to any one of embodiments 1 to 22, wherein step a) and subsequent step b1 ) are carried out in one pot.

[0110] 28. The process according to embodiment 1, wherein step a) is followed by step b2).

[0111] 29. The process according to embodiment 1 or 28, wherein the reaction in step b2) is carried out by continuously feeding the compound of formula I and chloroacetyl chloride into a continuous flow reactor.

[0112] 30. The process according to embodiments 1 and 28 to 29, wherein step b2) is carried out at a temperature of > -50 °C to < 50 °C.

[0113] 31. The process according to any one of embodiments 1 and 28 to 30, wherein step b2) is carried out at a temperature of > -40 °C to < 20 °C.

[0114] 32. The process according to any one of embodiments 1 and 28 to 31, wherein step b2) is carried out at a temperature of 0 °C.

[0115] 33. The process according to any one of embodiments 1 and 28 to 32, wherein the molar ratio of chloroacetyl chloride to compound of formula I in step b2) is in the range of > 1.00 : 1.00 to < 5.00 : 1.00.

[0116] 34. The process according to any one of embodiments 1 and 28 to 33, wherein the molar ratio of chloroacetyl chloride to compound of formula I in step b2) is in the range of > 2.00 : 1.00 to < 3.5 : 1.00.

[0117] 35. The process according to any one of embodiments 1 and 28 to 34, wherein the molar ratio of chloroacetyl chloride to compound of formula I in step b2) is 3.00 : 1.00.

[0118] 36. The process according to any one of embodiments 1 and 28 to 37, step b2) is carried out in at least one solvent selected from the group consisting of tetrahydrofuran, dimethoxyethane, toluene and mixtures thereof, preferably in a mixture of tetrahydrofuran, dimethoxyethane, toluene.

[0119] 37. The process according to any one of embodiments 1 and 28 to 38, step b2) is carried out in the solvent tetrahydrofuran.

[0120] 38. The process according to any one of embodiments 1 and 28 to 39, wherein the surface of the inner wall of the continuous flow reactor in step b2) is made of stainless steel or Hastelloy. Example

[0121] The present application is illustrated in detail by the following non-limiting examples.

[0122] Method

[0123] Characterization is carried out by combined high performance liquid chromatography / mass spectrometry (HPLC / MS), gas chromatography (GC), by NMR or by melting point.

[0124] HPLC method: Agilent Eclipse XDB-C18, 150 mm x 4.6 mm ID x 5 um

[0125] Gradient A = 0.5% H2SO4 in water, B = acetonitrile

[0126] Flow = 1.1 mL / min, column oven temperature = 30 °C

[0127] Gradient program = 20% B - 100% B - 15 min

[0128] Run time = 15 min

[0129] LCMS Method 1 : C18 column (50 mm x 2.1 mm x 1.7 pm)

[0130] Gradient A = 0.1 % TFA in water, B = acetonitrile

[0131] Flow = 0.8 mL / min to 1.0 mL / min over 1.5 min, column oven temperature = 60 °C

[0132] Gradient program = 10% B to 100% B over 15 min, hold 1 min 100% B, 1 min to 10% B

[0133] Run time: 1.75 min

[0134] 1 H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity, and by their integration (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m = multiplet, q = quadruplet, t = triplet, d = doublet, and s = singlet.

[0135] The abbreviations used are: h hours, min minutes, rt retention time, and ambient temperature 20-25 °C. Example 1 : Preparation of 2-chloro-1 -(2-chlorothiazol-5-yl)ethanone:

[0136] Step a) Preparation of the compound of formula I:

[0137]

[0138] Dissolve 50 g (98%, 1.0 eq) of 2-chlorothiazole in 110 g of dimethoxyethane (3.0 eq) and cool to 0 °C. Add 234 g of isopropylmagnesium chloride solution (ca. 20% in THF, 1.10 eq) over 2 hours with propane formation. Warm the reaction mixture to room temperature and stir overnight. Monitor for the formation of I by quenching an aliquot with iodine. The formed 2-chloro-5-iodothiazole is analyzed by HPLC (RT 9.7 min) and LC / MS (RT 1.05 min, [M+H] + 246) analysis.

[0139] Step b1 ): Reacting the compound of formula (I) with chloroacetyl chloride in a batch reactor:

[0140] The reaction mixture of step a) was dosed into a solution of 138 grams of chloroacetyl chloride (3 equivalents) in 94 grams of toluene at -50°C. After 30 minutes the mixture was warmed to -20°C and quenched with 149 grams of aqueous HCI (5%, 0.5 equivalents) over 30 minutes. The biphasic mixture was warmed to room temperature and the layers were separated. The aqueous phase was re-extracted with toluene and the organic phases were combined and washed with 10% aqueous sodium carbonate and water. The solution was concentrated under vacuum (291 grams, -21% by weight, 76% yield). δ (ppm) = 4.5, s, 2H; 8.25, s. 1H.

[0141] The following table 1 gives an overview of the different addition rates. All examples were carried out in the same way as example 1. However, in each case the addition rate of chloroacetyl chloride and the reaction temperature were varied. An unknown impurity was detected.

[0142] Table 1

[0143] Example Equivalent of chloroacetyl chloride Temperature [°C] Time of addition in Hrs Yield [%] 2 2 -70 2 66 3 2 -40 2 73 4 1.5 -50 2 70 5 3 -50 2 76 6 3 0 2 66 7 3 -20 2 69 8 3 -50 6 73 9 3 -50 8 73 10 3 -50 0.5 78

[0144] Example 2: Preparation of 2-chloro-l-(2-chlorothiazol-5-yl)ethenone:

[0145] Step a) Preparation of the compound of formula I:

[0146]

[0147] Dissolve 50 grams (98%, 1.0 equivalents) of 2-chlorothiazole in 110 grams of dimethoxyethane (3.0 equivalents) and cool to 0°C. Add 234 grams of isopropylmagnesium chloride solution (20% in THF, 1.10 equivalents) over 2 hours with propane formation. Warm the reaction mixture to room temperature and stir overnight. Check for the formation of I by quenching an aliquot with iodine. The formed 2-chloro-5-iodo-thiazole is analysed by HPLC (RT 9.7 min) and LC / MS (RT 1.05 min, [M+H] + 246).

[0148] Step b2): Reaction of the compound of formula (I) with chloroacetyl chloride in a continuous flow reactor:

[0149] Setup:

[0150] - HPLC pump controlled by mass flow controllers

[0151] - pressure damper

[0152] - stainless steel tubing

[0153] - passive mixer

[0154] - cryostat for temperature control

[0155] - the reactor tube and the mixer are immersed in a back-tempering bath of the cryostat

[0156] Starting materials:

[0157] - Formula I (component A):

[0158]

[0159] in dimethoxyethane and tetrahydrofuran;

[0160] - Component B:

[0161]

[0162] chloroacetyl chloride in toluene.

[0163] - Component C: tetrahydrofuran.

[0164] Results:

[0165] Variation of the synthesis temperature:

[0166] Equivalent of chloroacetyl chloride Component A Component B T synthesis Main product mol / mol ml / min ml / min ℃ ar % HPLC 3.9 7.3 9.6 -40 92 2.6 7.3 6.3 -40 89 3.9 7.3 9.6 -20 92 2.6 7.3 6.3 -20 92 3.9 14.6 19.2 -20 93 3.9 7.3 9.6 0 92 2.6 7.3 6.3 0 92 3.9 7.3 9.6 20 92 2.6 7.3 6.3 20 90 3.9 7.3 9.6 20 93 3.9 3.7 4.8 20 92 3.9 11.0 14.4 20 93

[0167] Variation of the molar ratio at constant synthesis temperature of 0°C:

[0168] Equivalent of chloroacetyl chloride Component A Component B Yield mol / mol g / min g / min ％ 3 10 6.5 76 4 10 8.7 77 5 10 10.9 76 3 20 10.9 76 3 20 13.0 77 3 10 6.5 74 4 20 17.4 81

Claims

1. A method for preparing 2-chloro-1-(2-chlorothiazol-5-yl)ethyl ketone, comprising at least the following steps: a) Preparation of compound I by reaction of 2-chlorothiazol with RMgX, wherein R is a C1-C6 alkyl group. Where X is a halogen; b1) React the compound of formula (I) with chloroacetyl chloride in a batch reactor; or b2) React the compound of formula (I) with chloroacetyl chloride in a continuous flow reactor.

2. The method of claim 1, wherein R in step a) is isopropyl.

3. The method according to claim 1, wherein X in step a) is Cl.

4. The method according to claim 2, wherein X in step a) is Cl.

5. The method according to any one of claims 1-4, wherein RMgX in step a) is isopropyl magnesium chloride.

6. The method according to any one of claims 1-4, wherein in step a) RMgX and 2-chlorothiazol are used in a molar ratio in the range of ≥0.9:1.00 to ≤1.3:1.

00.

7. The method of claim 5, wherein in step a) RMgX and 2-chlorothiazol are used in a molar ratio in the range of ≥0.9:1.00 to ≤1.3:1.

00.

8. The method according to any one of claims 1-4, wherein the reaction in step a) is carried out in at least one solvent selected from tetrahydrofuran, dimethoxyethane and mixtures thereof.

9. The method of claim 7, wherein the reaction in step a) is carried out in at least one solvent selected from tetrahydrofuran, dimethoxyethane, and mixtures thereof.

10. The method of claim 8, wherein the reaction in step a) is carried out in a mixture of tetrahydrofuran and dimethoxyethane.

11. The method according to any one of claims 1-4, wherein in step a), isopropyl magnesium chloride is added as a THF solution to 2-chlorothiazol.

12. The method of claim 10, wherein in step a), the initial concentration of 2-chlorothiazol in dimethoxyethane is in the range of ≥119 g / L to ≤790 g / L.

13. The method according to any one of claims 1-4, wherein the reaction in step a) is carried out at a temperature of ≥-20°C to ≤40°C.

14. The method of claim 1, wherein step b1) follows step a).

15. The method of claim 1, wherein in step b1), chloroacetyl chloride and the compound of formula (I) are used in a molar ratio in the range of ≥1.00:1.00 to ≤5.00:1.

00.

16. The method of claim 14, wherein in step b1), chloroacetyl chloride and the compound of formula (I) are used in a molar ratio in the range of ≥1.00:1.00 to ≤5.00:1.

00.

17. The method according to any one of claims 1 and 14-16, wherein step b1) is carried out in at least one solvent selected from toluene, tetrahydrofuran, dimethoxyethane, xylene, ethylbenzene, chlorobenzene, methyl tert-butyl ether, and mixtures of two or more of these.

18. The method according to any one of claims 1 and 14-16, wherein step b1) is carried out in at least one solvent selected from toluene, tetrahydrofuran, dimethoxyethane, and mixtures of two or more of these.

19. The method according to any one of claims 1 and 14-16, wherein step b1) is performed at a temperature of ≥-70°C to ≤-35°C.

20. The method according to any one of claims 1 and 14-16, wherein step b1) is performed at a temperature of ≥-60°C to ≤-40°C.

21. The method according to any one of claims 1 and 14-16, wherein step b1) is performed at a temperature of ≥-52°C to ≤-48°C.

22. The method according to any one of claims 1-4, wherein steps a) and b1) are carried out in a single-pot reaction.

23. The method of claim 1, wherein step b2) follows step a).

24. The method of claim 1, wherein step b2) is carried out by continuously feeding the compound of formula (I) and chloroacetyl chloride into a continuous flow reactor.

25. The method of claim 23, wherein step b2) is carried out by continuously feeding the compound of formula (I) and chloroacetyl chloride into a continuous flow reactor.

26. The method according to any one of claims 1 and 23-25, wherein step b2) is performed at a temperature of ≥-50°C to ≤50°C.

27. The method according to any one of claims 1 and 23-25, wherein in step b2), chloroacetyl chloride and the compound of formula (I) are used in a molar ratio in the range of ≥1.00:1.00 to ≤5.00:1.

00.

28. The method according to any one of claims 1 and 23-25, wherein step b2) is carried out in at least one solvent selected from tetrahydrofuran, dimethoxyethane and mixtures thereof.

29. The method according to any one of claims 1 and 23-25, wherein the surface of the inner wall of the continuous flow reactor in step b2) is made of stainless steel or Hastelloy.

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