Method for synthesizing 2-chloro-5-methylthiazole based on continuous flow method

Abstract

The invention discloses a method for rapidly synthesizing a key intermediate 2-chloro-5-methylthiazole of thiamethoxam, clothianidin and imidaclothiz based on a continuous flow method. According to the method, 2-amino-5-methylthiazole is taken as a raw material, and efficient synthesis of 2-chloro-5-methylthiazole is realized through a microreactor and a tubular reactor in the presence of sodium nitrite and a hydrochloric acid aqueous solution under mild conditions. According to the method, a continuous flow strategy is adopted to overcome the defects of potential production safety hazards, reduced reaction efficiency and the like caused by strong heat release in the diazonium salt generation process, expensive reagents are not needed, solvents and energy are saved, and a feasible solution is provided for industrial production of 2-chloro-5-methylthiazole.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing 2-chloro-5-methylthiazole based on a continuous flow method, particularly relating to a method for synthesizing 2-chloro-5-methylthiazole, a key intermediate in the pesticides thiamethoxam, thiamethoxam, and chlorothiazoline. Background Technology

[0002] 2-Chloro-5-methylthiazole is an essential intermediate in the synthesis of various highly effective neonicotinoid insecticides (such as thiamethoxam, thiamethoxam, and chlorothiazoline). The methyl group at the 5-position and the highly reactive chlorine atom at the 2-position of the thiazole ring in the compound's molecular structure provide crucial linking and reaction sites for the subsequent construction of complex insecticide molecules. Industrially, the Sandmeyer reaction is commonly used to prepare 2-chloro-5-methylthiazole. This reaction starts with 2-amino-5-methylthiazole, which reacts with sodium nitrite under acidic conditions (usually hydrochloric acid) to generate a diazonium salt intermediate. This intermediate is then substituted with a chlorine atom under cuprous chloride catalysis or direct thermal decomposition to obtain the target product. Although this traditional method is relatively mature, it often faces problems in batch reactor reactions, such as the instability of the diazonium salt, intense exothermic reaction, numerous byproducts, yield fluctuations, and safety concerns, limiting its industrial application.

[0003]

[0004] Currently, several studies have reported different improvement schemes. Zhejiang Yongtai Technology Co., Ltd., in its patent document (CN108276357A), used tert-butylthiocyanate as the diazotizing agent to achieve the conversion of 2-amino-5-methylthiazole to 2-chloro-5-methylthiazole under the catalysis of anhydrous copper chloride. However, this method requires the prior preparation of tert-butylthiocyanate, which is costly, and it relies on anhydrous copper chloride as a catalyst, increasing production costs and operational complexity. Batra et al. (Chem. Eur. J. 2018, 24, 14622-14626) reported a method using a combination of chlorosuccinimide and sodium nitrite for the Sandmeyer reaction, but the chlorosuccinimide used in this method is expensive, and the reaction solvent is DMF, resulting in high costs and cumbersome post-processing, making it difficult to meet the requirements of industrial production. Chengdu Qianye Longhua Petroleum Engineering Technology Consulting Co., Ltd. proposed a method using cuprous chloride as the chlorine source and o-chlorotoluene and hexane as solvents in patent document (CN105622542A). While this method can synthesize the target product, it uses a large amount of organic solvent and has a long reaction time, resulting in low efficiency and significant environmental and safety concerns. GlaxoSmithKline (WO2015 / 136463A1) reported a method for diazotization using sodium nitrite aqueous solution and concentrated hydrochloric acid by slow dropwise addition at low temperature (minus five degrees Celsius). Although this method is low-cost, the strong exothermic reaction during diazonium salt formation necessitates slow dropwise addition to avoid violent reactions, posing safety risks for industrial production and reducing reaction efficiency.

[0005] In recent years, the rapid development of continuous flow synthesis technology has brought revolutionary changes to the field of chemical synthesis. This technology, through the use of microreactors, increases specific surface area and accelerates reaction rates, thereby significantly shortening reaction time and improving production efficiency. Compared with traditional batch reactions, continuous flow reaction systems have smaller liquid hold-up, thus improving safety, and are particularly suitable for handling some high-risk reactions. By precisely controlling the reaction temperature and time, continuous flow technology can not only improve reaction yields and reduce by-product formation, but also reduce purification difficulty and environmental pollution. Therefore, this technology is of great significance in optimizing reaction processes and improving the level of green chemistry.

[0006] In conclusion, in order to meet the higher requirements of industrial production in terms of cost, efficiency and safety, there is an urgent need to develop a chemical reaction technology that is lower in cost, higher in reaction efficiency, safer and more environmentally friendly, especially for its application in highly reactive systems. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, including the instability of diazonium salts, intense exothermic reactions, numerous byproducts, yield fluctuations, and safety issues, this invention provides a synthetic method for synthesizing 2-chloro-5-methylthiazole based on a continuous flow process.

[0008] In one specific embodiment, this invention proposes a method for the efficient synthesis of 2-chloro-5-methylthiazole using 2-amino-5-methylthiazole as a raw material, in the presence of sodium nitrite and hydrochloric acid aqueous solution, under mild conditions, via a microreactor and a tubular reactor. This continuous flow strategy overcomes the drawbacks of the diazonium salt formation process, such as production safety hazards and reduced reaction efficiency due to strong exothermic reactions. It eliminates the need for expensive reagents, saves solvents and energy, and provides a practical solution for the industrial production of 2-chloro-5-methylthiazole.

[0009] This invention provides a rapid synthesis of 2-chloro-5-methylthiazole using a continuous flow method. The method uses 2-amino-5-methylthiazole as a raw material and, in the presence of sodium nitrite and hydrochloric acid aqueous solution, prepares 2-chloro-5-methylthiazole through a two-step continuous flow reaction of diazotization and chlorination (in one specific embodiment, via a microreactor and tubular reactor, etc.), achieving highly efficient synthesis of 2-chloro-5-methylthiazole. The process directly generates diazonium salts in situ, which are then consumed immediately, avoiding the accumulation of diazonium salts and preventing runaway reactions. The reaction route is shown below:

[0010]

[0011] In the method, the concentrations of the reactants are as follows: the concentration of 2-amino-5-methylthiazole (compound 1) is 1.0 mol / L-4.0 mol / L, the concentration of sodium nitrite is 1.5 mol / L-3.0 mol / L, and the concentration of hydrochloric acid is 3.0 mol / L-6.0 mol / L.

[0012] In the method, the reaction temperatures are as follows: the temperature of the first stage reaction is 5-20℃; the reaction temperature of the second stage reaction is 50℃-90℃.

[0013] In the method, the reaction times are as follows: the first reaction time is 10s-180s; the second reaction time is 3min-6min.

[0014] In the method described, the initial pressure of the reaction is 0.5-1.0 mPa.

[0015] The method employs a continuous flow apparatus, which includes: a microreactor, a continuous flow reaction tube, a temperature control system, a continuous flow reaction experimental pump, a continuous flow reaction pressure stabilizer, and a continuous flow product collection device; wherein...

[0016] Microreactors are used for diazotization reactions;

[0017] Continuous flow reaction tube, used for chlorination reactions;

[0018] Temperature control system for temperature control in a two-step reaction;

[0019] A continuous flow reaction experimental pump, used to connect to the inlet of the reactants;

[0020] Continuous flow reaction pressure regulator, used to connect to the product outlet;

[0021] A continuous flow product collection device is connected to the outlet of the pressure stabilizing device.

[0022] The microreactor includes one or more of the following: tubular reactor, heart-shaped reactor, V-shaped reactor, and 3D reactor; preferably, it is a 3D reactor. The inner diameter of the heart-shaped reactor, V-shaped reactor, and 3D reactor is 550 μm to 750 μm; the inner diameter of the tubular reactor is 1-3 mm, preferably 2 mm.

[0023] In the method, the material of the continuous flow reaction tube includes one or more of PTFE Teflon tubes, PFA Teflon tubes, etc.; the material of the heart-shaped reactor, V-shaped reactor, and 3D reactor is quartz glass.

[0024] In the method, the total reaction time is 3-8 minutes, preferably 5 minutes.

[0025] In the method, the separation yield is greater than 60%.

[0026] The present invention also provides the application of the method described above in the efficient synthesis of 2-chloro-5-methylthiazole, the efficient synthesis of key intermediates of thiamethoxam, thiamethoxam and chlorothiazoline, and the industrial production of 2-chloro-5-methylthiazole.

[0027] The beneficial effects of this invention are as follows: This invention proposes a method for the rapid synthesis of 2-chloro-5-methylthiazole, a key intermediate of thiamethoxam, thiamethoxam, and chlorothiazoline, based on a continuous flow approach. The method uses 2-amino-5-methylthiazole as a raw material, and achieves efficient synthesis of 2-chloro-5-methylthiazole under mild conditions in the presence of sodium nitrite and hydrochloric acid aqueous solution, via a microreactor and a tubular reactor. The continuous flow strategy overcomes the disadvantages of production safety hazards and reduced reaction efficiency caused by the strong exothermic reaction during diazonium salt formation. It eliminates the need for expensive reagents, saves solvents and energy, and provides a practical solution for the industrial production of 2-chloro-5-methylthiazole. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 This is a schematic diagram of the process flow for synthesizing 2-chloro-5-methylthiazole according to the present invention.

[0030] Figure 2 Experimental diagram of the process for synthesizing 2-chloro-5-methylthiazole according to the present invention. Detailed Implementation

[0031] To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to preferred embodiments. It should be noted that the described embodiments are only some embodiments of the present invention, and not all embodiments. The following preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

[0032] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0033] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0034] This invention discloses a method for the rapid synthesis of 2-chloro-5-methylthiazole, a key intermediate in thiamethoxam, thiamethoxam, and chlorothiazoline, using a continuous flow approach. The synthesis method uses 2-amino-5-methylthiazole as a raw material and, under mild conditions in the presence of sodium nitrite and hydrochloric acid aqueous solution, achieves efficient synthesis of 2-chloro-5-methylthiazole via a microreactor and a tubular reactor. This continuous flow strategy overcomes the drawbacks of diazonium salt formation, such as production safety hazards and reduced reaction efficiency due to strong exothermic reactions. It eliminates the need for expensive reagents, saves solvents and energy, and provides a practical solution for the industrial production of 2-chloro-5-methylthiazole.

[0035] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0036] Example 1:

[0037] As attached Figure 1 As shown, compound 1 (2-amino-5-methylthiazole) (5.0 g, 0.044 mol, 1.0 eq.), HCl (21.9 g, 0.22 mol, 5.0 eq.), and water (5 g) were prepared into a 30 mL 1.46 mol / L solution as feed 1; sodium nitrite (3.57 g, 0.052 mol, 1.0 eq.) and water (25 g, 5V) were prepared into a 26 mL 2.0 mol / L solution as feed 2; feed 1 and feed 2 were injected into the reaction system through pumps P1 and P2, respectively, at flow rates of 5.36 mL / min and 4.64 mL / min, respectively. The mixture first passed through a V-type reactor (10 mL, 570 μm–750 μm) at 15 °C for 1 min. Then, the entire reaction solution flowed into a second delay tube at 70 °C for 4.8 min. CH₂Cl₂ was then introduced into the reaction system at a rate of 10 mL / min and separated by a liquid-liquid separator to obtain the organic phase. The initial pressure of the system was 0.8 MPa. The organic phase was monitored by NMR, and its yield was 65% (using 1,1,2,2-tetrachloroethane as an internal standard). The organic phase was evaporated to dryness and then passed through a column to give 3.24 g of a colorless oily product, with a separation yield of 55%.

[0038] 1 HNMR(400MHz,Chloroform-d)δ7.21(s,1H),2.42(s,3H).

[0039] 13 C NMR(100MHz,Chloroform-d)δ149.35,138.83,136.04,12.21.

[0040] Example 2:

[0041] The V-type reactor was replaced with a tubular reactor, and the rest of the operation was the same as in Embodiment 1 of the present invention; the reaction time was 90s and the NMR yield was 56%.

[0042] Example 3:

[0043] The V-shaped reactor was replaced with a heart-shaped reactor, and the remaining operations and parameters were the same as in Embodiment 1 of the present invention; the reaction time was 60 s and the NMR yield was 60%.

[0044] Example 4:

[0045] The V-shaped reactor was replaced with a heart-shaped reactor, and the remaining operations and parameters were the same as in Embodiment 1 of the present invention; the reaction time was 15s and the NMR yield was 70%.

[0046] Example 5:

[0047] The reaction temperature of the first stage was changed to 5℃, 10℃, 20℃, and 25℃, and the remaining operations and parameters were the same as in Example 1 of this invention; the NMR yields were 40%, 60%, 45%, and 42%, respectively.

[0048] Example 6:

[0049] The reaction temperature of the second stage was changed to 55℃, 60℃, 65℃, and 75℃, and the remaining operations and parameters were the same as in Example 1 of this invention; the NMR yields were 42%, 55%, 60%, and 65%.

[0050] Example 7:

[0051] The equivalents of hydrochloric acid were changed to 2 eq., 3.0 eq., 4.0 eq., and 6.0 eq., and the remaining operations and parameters were the same as in Example 1 of this invention; the NMR yields were 30%, 45%, 58%, and 60%.

[0052] Example 7:

[0053] The initial reaction pressures were changed to 0.2 MPa, 0.4 MPa, 0.6 MPa, and 1.0 MPa, with all other operations and parameters remaining the same; the NMR yields were 40%, 50%, 58%, and 63%.

[0054] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0055] As used in this invention, the term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0056] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0057] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept, as well as any simple technical modifications or equivalent substitutions made by those skilled in the art, are included in this invention and are protected by the appended claims.

Claims

1. A method for the rapid synthesis of 2-chloro-5-methylthiazole based on a continuous flow process, characterized in that, The method uses 2-amino-5-methylthiazole as a raw material and prepares 2-chloro-5-methylthiazole through a two-step continuous flow reaction of diazotization and chlorination in the presence of sodium nitrite and hydrochloric acid aqueous solution. The reaction route of the method is shown below:

2. The method according to claim 1, characterized in that, The concentration of the 2-amino-5-methylthiazole is 1.0 mol / L to 4.0 mol / L; and / or the concentration of the sodium nitrite is 1.5 mol / L to 3.0 mol / L; and / or the concentration of the hydrochloric acid is 3.0 mol / L to 6.0 mol / L.

3. The method according to claim 1, characterized in that, The temperature of the first stage reaction is 5-20℃; and / or the temperature of the second stage reaction is 50℃-90℃.

4. The method according to claim 1, characterized in that, The first reaction segment lasts for 10-180 seconds; and / or the second reaction segment lasts for 3-6 minutes.

5. The method according to claim 1, characterized in that, The initial pressure of the reaction is 0.5 mPa to 1.0 mPa.

6. The method according to claim 1, characterized in that, The method employs a continuous flow apparatus, which includes: a microreactor, a continuous flow reaction tube, a temperature control system, a continuous flow reaction experimental pump, a continuous flow reaction pressure stabilizer, and a continuous flow product collection device; wherein... The microreactor is used for the diazotization reaction; The continuous flow reaction tube is used for the chlorination reaction; The temperature control system is used for temperature control of the two-step reaction. The continuous flow reaction experimental pump is used to connect to the inlet of the reactants; The continuous flow reaction pressure stabilizing device is used to connect to the product outlet; The continuous flow product collection device is connected to the outlet of the pressure stabilizing device.

7. The method according to claim 5, characterized in that, The microreactor includes one or more of the following: tubular reactor, heart-shaped reactor, V-shaped reactor, and 3D reactor; wherein the inner diameter of the heart-shaped reactor, V-shaped reactor, and 3D reactor is 550μm to 750μm, and the inner diameter of the tubular reactor is 1mm to 3mm.

8. The method according to claim 5, characterized in that, The continuous flow reaction tube is made of one or both of the following materials: PTFE Teflon tube and PFA Teflon tube; the heart-shaped reactor, V-shaped reactor, and 3D reactor are made of quartz glass.

9. The method according to claim 1, characterized in that, The total reaction time of the method is 3-8 min; and / or the separation yield of the method is greater than 60%.

10. The application of the method according to any one of claims 1-9 in the efficient synthesis of 2-chloro-5-methylthiazole, the efficient synthesis of key intermediates of thiamethoxam, thiamethoxam, and chlorothiazoline, and in the industrial production of 2-chloro-5-methylthiazole.

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