Method for synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole based on continuous streamer reaction
The synthesis of 2-chloro-5-chloromethylthiazole and/or 2-chloro-5-bromomethylthiazole via a continuous streaming photocatalytic reaction method solves the problems of high raw material costs, serious environmental issues, and low reaction efficiency in existing technologies, and achieves efficient and safe industrial production.
Patent Information
- Application Number
- CN202511352731.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-22
- Publication Date
- 2025-12-26
AI Technical Summary
The existing methods for synthesizing 2-chloro-5-chloromethylthiazole suffer from drawbacks such as high raw material costs, serious environmental problems, and low reaction efficiency, making it difficult to meet industrialization needs.
A continuous photocatalytic reaction method was adopted, using 2-chloro-5-methylthiazole as a raw material and N-chlorosuccinimide or N-bromosuccinimide as halogenating reagents, to carry out a chloro/bromomethylation reaction under light conditions in a continuous photocatalytic reactor to synthesize 2-chloro-5-chloromethylthiazole and/or 2-chloro-5-bromomethylthiazole.
This improved the reaction yield, overcame the difficulties in achieving high yields from photoreaction, and saved solvents and energy, providing a practical solution for the industrial production of 2-chloro-5-chloromethylthiazole and/or 2-chloro-5-bromomethylthiazole.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole based on a continuous streaming photoreaction method, particularly relating to a method for synthesizing 2-chloro-5-chloro(bromo)methylthiazole, a key intermediate in the pesticide insecticides thiamethoxam, thiamethoxam, and chlorothiazoline. Background Technology
[0002] Neonicotinoid insecticides are a class of insecticides characterized by safety, high efficiency, and high selectivity, with unique mechanisms of action and low mammalian toxicity. Thiamethoxam, thiamethoxam, and chlorothalonil (see Mechanism 1a) are representative second-generation neonicotinoid insecticides. In 2016, thiamethoxam's global sales reached $1.2 billion, ranking second in global insecticide sales. Thiamethoxam, subsequently introduced, has attracted considerable attention due to its broader insecticidal spectrum and longer-lasting residual effects, with a global market value of approximately $400 million. Despite recent restrictions on the use of insecticides such as imidacloprid and thiamethoxam in Europe and the United States, thiamethoxam's sales have remained stable. Chlorthylthylthion, an insecticide independently developed in China, possesses higher insecticidal activity, lower toxicity, a broad insecticidal spectrum, and is unaffected by temperature changes, thus showing broad application prospects in agricultural production.
[0003]
[0004] 2-Chloro-5-chloromethylthiazole is an important intermediate in the synthesis of three pesticide molecules: thiamethoxam, thiamethoxam, and chlorothiazoline. Currently, there are many methods for its synthesis, among which the main methods are as follows: The first method uses 2,3-dichloropropene as a raw material. This route has a high overall yield and is simple to operate, making it the main method for industrial production. However, its raw material cost is high, and it relies on chlorine and sulfonyl chloride, posing environmental pollution problems. The second method uses propargylamine as a raw material, with an overall yield reaching 73%, but... The first method uses expensive raw materials, making it uneconomical, and relies on chlorine and sulfonyl chloride, posing environmental pollution problems. The second method uses 2-chloropropeneamine as a raw material, but the process is lengthy, requiring indirect preparation of the raw material via 2,3-dichloropropene, and involves large amounts of sulfonyl chloride, resulting in acidic waste liquid. The third method uses 2-chloropropene as a raw material, but the overall yield is only 42.1%, and the product purity is 42.4%, both of which are insufficient for industrial-scale applications. The fifth method (using allyl aldehyde as a raw material) involves hazardous chemicals and diazotization reactions, posing a high risk of industrial scale-up. Therefore, developing a new synthetic route that uses economical raw materials, employs green procedures, is safe to operate, and achieves ideal yields remains a significant challenge in this field.
[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 summary, in order to overcome the shortcomings of existing technologies such as high raw material costs, serious environmental problems, and low reaction efficiency, developing a green, safe, and efficient synthesis method is an urgent technical problem to be solved. Summary of the Invention
[0007] To overcome the shortcomings of existing technologies, including the corrosiveness to equipment, the toxicity of reagents, and safety, this paper provides a method for synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole based on a continuous streaming photoreaction method.
[0008] This invention utilizes 2-chloro-5-methylthiazole as a starting material and N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) as a halogenating agent to rapidly synthesize 2-chloro-5-chloro(bromo)methylthiazole by combining continuous flow technology with photochemical reaction. This continuous flow strategy not only improves the reaction yield but also overcomes the difficulty of achieving high yields in photoreactions, while simultaneously saving solvents and energy. It provides a practical solution for the industrial production of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole.
[0009] This invention provides a method for synthesizing the key intermediates 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole from thiamethoxam, thiamethoxam, and chlorothiazoline using a continuous photocatalytic reaction. The method uses 2-chloro-5-methylthiazole and a chloro / bromomethylating agent as raw materials. In a solvent under light irradiation, a chloro / bromomethylation reaction occurs in a continuous photocatalytic reactor to prepare 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole. This method achieves highly efficient synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole, with a separation yield of 2-chloro-5-bromomethylthiazole exceeding 85%. The reaction route is shown below:
[0010]
[0011] In the method, the chlorine / bromomethylation reagent includes one or more of N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), chlorine gas, liquid bromine, etc.
[0012] In the method, the solvent includes one or more of the following: chloroform, acetonitrile, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, acetic acid, etc.; preferably, it is acetonitrile.
[0013] In the method, the molar ratio of 2-chloro-5-methylthiazole to the chloro / bromomethylating agent is 1:1-1.5; preferably, it is 1:1.1.
[0014] In the method, the reaction temperature of the chloro / bromomethylation reaction (compound 1 to compound 2) is 0°C to 40°C; preferably, it is 20°C.
[0015] In the method, the retention time of the chloro / bromomethylation reaction is 20 min–60 min; preferably, it is 30 min.
[0016] In the method, the wavelength of the light source is between 360nm and 450nm; preferably, it is 390nm.
[0017] In the method, the power of the light source is between 12W and 100W; preferably, it is 40W.
[0018] The method employs a continuous flow apparatus, which includes: a continuous flow reactor, a temperature control system, a continuous flow experimental pump, and a continuous flow product collection device; wherein...
[0019] The continuous flow reactor is used for the chlorination / bromomethylation reaction;
[0020] The temperature control system is used to control the chloro / bromomethylation reaction;
[0021] The continuous flow reaction experimental pump is used to connect to the inlet of the reactants;
[0022] The continuous flow product collection device is connected to the outlet of the reaction liquid.
[0023] The continuous flow reactor is made of one or more of the following materials: PTFE Teflon tubing, PFA Teflon tubing, etc.; preferably, it is PFA Teflon tubing.
[0024] The inner diameter of the continuous flow reactor is 0.8 mm to 2 mm; preferably, it is 2 mm.
[0025] In the method, the overall reaction time is 20 min to 60 min; preferably, it is 30 min.
[0026] In the method, the separation yield of bromomethylation reaches over 85%.
[0027] The present invention also provides the application of the method described above in the efficient synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole, the efficient synthesis of key intermediates of thiamethoxam, thiamethoxam and chlorothiazoline, and the industrial production of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole.
[0028] The beneficial effects of this invention are as follows: This invention discloses a method for synthesizing the key intermediates 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole from thiamethoxam, thiamethoxam, and chlorothiazoline using a continuous flow photoreactor. The method uses 2-chloro-5-methylthiazole and N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) as raw materials, and achieves the efficient synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole under illumination via a photoreactor. The continuous flow strategy employed in this method not only improves the reaction yield but also overcomes the difficulty of achieving high-yield photoreactor reactions, while simultaneously saving solvents and energy, providing a practical solution for the industrial production of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole. Attached Figure Description
[0029] 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.
[0030] Figure 1 This is a schematic diagram of the process flow for synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole according to the present invention.
[0031] Figure 2 This is a process experiment diagram of the synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole according to the present invention. Detailed Implementation
[0032] 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, not all embodiments, and the following preferred embodiments should not be considered as limitations on the present invention. 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.
[0033] 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.
[0034] 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.
[0035] This invention discloses a method for synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole, key intermediates of thiamethoxam, thiamethoxam, and chlorothiazoline, based on a continuous-flow photoreactor approach. The method uses 2-chloro-5-methylthiazole and N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) as raw materials. Under illumination, the mixture passes through a photoreactor, achieving efficient synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole. The continuous-flow strategy employed in this method not only improves the reaction yield but also overcomes the difficulty of achieving large-scale photoreactor reactions, while simultaneously saving solvents and energy. This provides a practical solution for the industrial production of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole.
[0036] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.
[0037] Example 1:
[0038] A 40 mL 0.62 M mixed solution was prepared from compound 1 (3.30 g, 0.0246 mol 1.0 eq), NCS (3.29 g, 0.0264 mol 1.05 eq), and MeCN (acetonitrile) (330 g). The mixed solution was pumped into a photoreactor (PTFE, 2 mm diameter, 3 mm outer diameter, 45 mL, hv = 390 nm) at 20 °C and a flow rate of 1.5 mL / min. After a residence time of 30 min, the mixture was introduced into the system via a T-type filter with a solution of EtOAc and NaHCO3 (aq.) (4:1, flow rate: 10 mL / min). The mixture was then separated by a liquid-liquid membrane separator. The organic phase was collected and concentrated. The crude product was monitored by NMR (yield: 72%, with 1,1,2,2-tetrachloroethane as an internal standard). The residue was purified by column chromatography (PE / EA = 80 / 1) to give a pale yellow oily compound, 2-chloro-5-chloromethylthiazole (2.67 g, 65%).
[0039] 1 H NMR (400MHz, CDCl3) δ7.48(s,1H), 4.69(s,2H)
[0040] Example 2:
[0041] A 40 mL 0.62 M mixed solution was prepared from compound 1 (3.30 g, 0.0246 mol, 1.0 eq.), NBS (4.70 g, 0.0264 mol, 1.05 eq.), and MeCN (33 g). The mixed solution was pumped into a photoreactor (PTFE, 2 mm diameter, 3 mm outer diameter, 45 mL, hv = 390 nm) at 20 °C and a flow rate of 1.5 mL / min. After a residence time of 30 min, the mixture was introduced into the system via a T-type filter with a solution of EtOAc and NaHCO3 (aq.) (4:1, flow rate: 10 mL / min). The mixture was then separated by a liquid-liquid membrane separator. The organic phase was collected and concentrated. The crude product was monitored by NMR (yield: 92%, with 1,1,2,2-tetrachloroethane as an internal standard). The residue was purified by column chromatography (PE / EA = 80 / 1) to give a pale yellow oily compound, 2-chloro-5-bromomethylthiazole (4.25 g, 82%).
[0042] 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 4.61 (s, 2H).
[0043] Example 3:
[0044] 400 mL of 0.62 M solution was prepared from compound 1 (33.0 g, 0.246 mol 1.0 eq), NBS (47.0 g, 0.264 mol 1.05 eq), and ACN (330 g). The solution was then pumped into a photoreactor (PTFE, 2 mm diameter, 3 mm spacing, 45 mL, hv = 390 nm) and immersed in a thermostat (20 °C) at a flow rate of 1.5 mL / min. After a residence time of 30 min, the mixture was connected to a T-connector with a solution of EtOAc and NaHCO3 (aq.) (4:1, flow rate: 10 mL / min). The mixture was then flowed into a liquid-liquid membrane separator, the organic layer was collected and concentrated, and the crude product was monitored by NMR (yield: 92% with 1,1,2,2-tetrachloroethane as an internal standard). The residue was purified by column chromatography (PE / EA = 80 / 1) to give 2-chloro-5-bromomethylthiazole (44.8 g, 85%).
[0045] Example 4:
[0046] When the reaction temperature of Example 2 of the present invention was increased to 30°C, 40°C, and 50°C, while other conditions remained unchanged, the yields were 75%, 60%, and 40%, respectively.
[0047] Example 5:
[0048] When the solvent in Example 2 of this invention was replaced with CHCl3, DCE (1,2-dichloroethane), and THF (tetrahydrofuran), and other conditions remained unchanged, the yields were 40%, 35%, and 15%, respectively.
[0049] Example 6:
[0050] When the light source in Embodiment 2 of the present invention is replaced with 365nm and 450nm, and other conditions remain unchanged, the yields are 40% and 20%, respectively.
[0051] 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.
[0052] 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.
[0053] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.
[0054] 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 synthesizing 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole based on a continuous streaming photoreaction method, characterized in that, The method uses 2-chloro-5-methylthiazole and a chloro / bromomethylating agent as raw materials. In a solvent, under light irradiation, a chloro / bromomethylation reaction occurs in a continuous flow photoreactor to prepare 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole. The reaction route of the method is shown below:
2. The method according to claim 1, characterized in that, The chloro / bromomethylating agent includes one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), chlorine, and liquid bromine; the solvent includes one or more of chloroform, acetonitrile, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, and acetic acid.
3. The method according to claim 1, characterized in that, The molar ratio of the 2-chloro-5-methylthiazole and the chloro / bromomethylating agent is 1:(1-1.5).
4. The method according to claim 1, characterized in that, The reaction temperature of the chloro / bromomethylation reaction is 0℃~40℃; and / or, the retention time of the chloro / bromomethylation reaction is 20min-60min.
5. The method according to claim 1, characterized in that, The wavelength of the light source is 360nm to 450nm; and / or the power of the light source is 12W to 100W.
6. The method according to claim 1, characterized in that, The method employs a continuous flow apparatus, which includes: a continuous flow photoreactor, a temperature control system, a continuous flow reaction experimental pump, and a continuous flow product collection device; wherein, the continuous flow reactor is used for the chlorination / bromomethylation reaction; The temperature control system is used for the chloro / bromomethylation reaction; The continuous flow reaction experimental pump is used to connect to the inlet of the reactants; The continuous flow product collection device is connected to the outlet of the reaction liquid.
7. The method according to claim 6, characterized in that, The material of the continuous flow reactor includes one or both of PTFE Teflon tubing and PFA Teflon tubing; and / or, the inner diameter of the continuous flow reactor is 0.8 mm to 2 mm.
8. The method according to claim 1, characterized in that, The total reaction time of the method is 20 min to 60 min.
9. The method according to claim 1, characterized in that, The separation yield of bromomethylation by the method reaches over 85%.
10. The application of the method according to any one of claims 1-9 in the efficient synthesis of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole, the efficient synthesis of key intermediates of thiamethoxam, thiamethoxam and chlorothiazoline, and the industrial production of 2-chloro-5-chloromethylthiazole and / or 2-chloro-5-bromomethylthiazole.