Method for preparing azamethiphos through one-pot method
Preparation of methylpyridine phosphorus through one-pot method simplifies the process flow, reduces production costs and equipment demands, increases the total yield, and solves the problems of complex synthesis processes and low total yields in the existing technology.
Patent Information
- Application Number
- CN202411671846.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-21
- Publication Date
- 2025-02-25
AI Technical Summary
The existing methylpyridine phosphorus synthesis process is complex, requiring multiple reactions and multiple impurity removal treatments, resulting in high production costs, large workload, large equipment demand, and low total yield.
The methylpyridine phosphorus was prepared by a one-pot method, and O,O-dimethylphosphorus phosphate was formed by reaction of sulfur and dimethylphosphorus esters, and then reacted with bromoiodine or chloroiodone to form S-(halomethyl)O,O-dimethylphosphorus esters, and finally reacted with 6-chloro-oxazole [4,5-b]pyridine-2(3H) ketone to form methylpyridine phosphorus.
It simplifies the production process, reduces labor workload and time costs, improves production efficiency, reduces equipment and site demand, and has a total yield of more than 80%, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present application relates to the field of preparation of methyl pyridinium phos, and in particular to a method for preparing methyl pyridinium phos in a one-pot process. Background Art
[0002] Methylpyridinium chloride is a chemical substance with the molecular formula C 9 H 10 C l N 2 O 5 PS, structural formula: Methyl pyridophos is a miticide and a broad-spectrum organophosphorus insecticide. It is highly effective, low-toxic and low-residue. It is a contact and stomach poison, but low-toxic to mammals. It is an organophosphorus insecticide recommended by the World Health Organization. It can kill pests resistant to pyrethroids and has significant effects on multi-resistant fly strains. It is widely used in public health and household control of various mites, cockroaches and flies. In the salmon farming industry, methyl pyridophos is also used as an ideal agent for comprehensive management of sea lice, which increases the demand for methyl pyridophos.
[0003] The method disclosed in Chinese patent CN1386741, which uses oxazol[4,5-b]pyridine-2(3H)one as a starting material, obtains 6-chloro-oxazol[4,5-b]pyridine-2(3H)one through chlorination, and then undergoes hydroxymethylation, chlorination, condensation and other reactions to synthesize methylpyridine phosphonium, is briefly summarized as follows: The first step is to use 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one, structural formula: As a raw material, first hydroxylate to obtain the product of reaction A, 3-hydroxymethyl-6-chloro-oxazolo[4,5-b]pyridine-2(3H)one, structural formula:
[0004] In the second step, the product of reaction A undergoes chlorination reaction to generate the product of reaction B, 3-chloromethyl-6-chloro-oxazolo[4,5-b]pyridin-2(3H)one, with the structural formula:
[0005] In the third step, the product of reaction B and O,O-dimethylammonium thiophosphate are dissolved in methanol and reacted to generate a crude methylpyridinium phosphite product.
[0006] In the fourth step, the crude methyl pyridophos product is refined to obtain a finished methyl pyridophos product with a content of 99%, and the yield can reach 78%.
[0007] In the above-mentioned synthesis process technical scheme of methyl pyridinium phosphide, each step needs to be treated with impurities, crystallized, filtered and dried after the reaction contact so as not to affect the subsequent reaction. The process is cumbersome. If it is applied to the industrial production of methyl pyridinium phosphide, the raw material cost is high, the workload is large, the equipment demand is large, and the production site demand is large. Summary of the invention
[0008] In order to facilitate the industrial application of methyl pyridine phosphide production, the present application provides a new synthetic route technical solution for preparing methyl pyridine phosphide by a one-pot method.
[0009] The present application provides a one-pot method for preparing methyl pyridinium phosphat, which adopts the following technical scheme: A method for preparing methyl pyridinium phosphide in one pot comprises the following steps: S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate; S2, O,O-dimethylthiophosphate reacts with bromoiodomethane or chloroiodomethane to form S-(halomethyl) O,O-dimethylthiophosphate, the structural formula is X=Br or Cl; S3, S-(halomethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate.
[0010] By adopting the technical scheme and a new synthetic route, sulfur and dimethyl phosphite react to generate O,O-dimethyl thiophosphate, O,O-dimethyl thiophosphate reacts with bromoiodomethane or chloroiodomethane to generate S-(halomethyl) O,O-dimethyl thiophosphate, and then reacts with 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one to finally generate methyl pyridinium phosphate, during which the yield of side reactions is small, and the side reaction products are not easy to affect the main reaction, so there is no need to perform filtering, washing, distillation and other operations after each reaction step, and multiple steps of reaction can be performed in the same container until the target product methyl pyridinium phosphate is generated, and finally the methyl pyridinium phosphate is purified to obtain methyl pyridinium phosphate with a purity of 98-99%, and the total yield reaches more than 80%.
[0011] The preparation scheme of methyl pyridinium in the scheme of the present application adopts a one-pot reaction. After the completion of step S1 and step S2, there is no need to replace the container, and there is no need to perform impurity removal operations such as filtration, washing, and distillation. The production process is greatly simplified, the manual workload is reduced, and the time cost is reduced, thereby greatly improving the production efficiency. Due to the reduction in the number of operating steps, the required equipment is also reduced, the equipment cost and the site cost are reduced, and the total yield of the target product is as high as 80%, making the method of methyl pyridinium in the scheme more suitable for industrial production.
[0012] Optionally, the following steps are included: S1, add sulfur, dimethyl phosphite and tetrahydrofuran as solvent into the reactor, start stirring, cool to -3-3°C, add sodium methoxide in batches, raise the temperature to 15-25°C, and keep the temperature to react until the end; the reaction formula is as follows: S2, control the temperature at 10-30°C, add bromoiodomethane or chloroiodomethane dropwise to the reaction solution obtained in S1, and after the addition is complete, continue the reaction at room temperature until completion; the reaction formula is as follows, wherein X is Cl or Br: S3, add 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and a tetrahydrofuran solution of a base to the reaction solution obtained in S2, and after the addition is complete, continue to heat and react until the reaction is complete; the reaction formula is as follows: S4, evaporating the reaction solvent from the reaction solution obtained in S3, adding methanol, stirring and heating to 35-45°C to dissolve, filtering out insoluble matter, controlling the temperature to 35-45°C, adding water dropwise to precipitate crystals, filtering and drying to obtain methyl pyridinium phosphide.
[0013] By adopting the above technical solution, the specific steps are simple, and the reaction temperature of S1-S3 does not exceed 50 degrees Celsius, making the production process safer and more suitable for industrial development.
[0014] Optionally, in S1, after adding sodium methoxide, the residual amount of dimethyl phosphite is monitored by thin layer chromatography to determine the end of the reaction.
[0015] By adopting the above technical solution, sampling during the reaction is convenient, the cost is low, and the detection is convenient, which makes it easy to confirm the reaction status.
[0016] Optionally, in step S3, after the dropwise addition of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and the tetrahydrofuran solution of the base is completed, thin layer chromatography is used to monitor the completion of the reaction of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one, and the reaction is terminated.
[0017] By adopting the above technical solution, it is convenient to confirm the reaction status so as to carry out the subsequent process and facilitate production.
[0018] Optionally, the base in S3 is one of sodium methoxide, N,N-diisopropylethylamine, triethylamine, potassium carbonate and sodium carbonate.
[0019] By adopting the above technical scheme, sodium methoxide, N,N-diisopropylethylamine, triethylamine, potassium carbonate and sodium carbonate can all promote the reaction and meet the reaction requirements.
[0020] Optionally, the molar ratio of sodium methoxide, sulfur and dimethyl phosphite in S1 is 1:1:1.
[0021] By adopting the above technical solution, under this ratio, the reaction effect is good, the conversion rate is high, and the raw materials are not easily wasted.
[0022] In summary, the present application includes at least one of the following beneficial technical effects: 1. The present application scheme adopts a new intermediate S-(halomethyl) O,O-dimethyl thiophosphate for reaction, so that the reaction time of the synthesis process of methyl pyridine phosphonate is short, and after the completion of step S1 and step S2, there is no need to replace the container, and there is no need to perform impurity removal operations such as filtration, washing, and distillation, which greatly simplifies the production process, reduces manual workload, and reduces time costs, thereby greatly improving production efficiency; due to the reduction of operating steps, the required equipment is also reduced, reducing equipment costs and site costs, and the total yield of the target product is as high as 80%, making the method of methyl pyridine phosphonate in this scheme more suitable for industrial production; 2. The reaction temperature of steps S1-S3 in the present application is relatively low, not exceeding 50 degrees Celsius, with low energy consumption and safe production process; 3. Since the reaction temperature is low, it is convenient to take samples, and it is convenient to use thin layer chromatography to monitor the progress of the reaction in steps S1 and S3, which is low in cost and easy to operate.
[0023] 4. The total reaction time of the application is short, usually 5-6 hours, and the production efficiency is high. DETAILED DESCRIPTION
[0024] The present application is further described in detail below with reference to the embodiments.
[0025] Ingredients 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one was purchased or synthesized. The synthesis method was based on step a of Example 1 of Chinese patent CN1386741.
[0026] Preparation Example Preparation Example 1 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one and sodium methoxide solution in tetrahydrofuran: 16.05 g of 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one and 5.95 g of sodium methoxide were dissolved in 50 mL of tetrahydrofuran.
[0027] Preparation Example 2 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one and N,N-diisopropylethylamine tetrahydrofuran solution: 16.05 g of 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one and 14.25 g of N,N-diisopropylethylamine were dissolved in 50 mL of tetrahydrofuran.
[0028] Preparation Example 3 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one and triethylamine tetrahydrofuran solution: 16.05 g of 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one and 11.15 g of triethylamine were dissolved in 50 mL of tetrahydrofuran.
[0029] Preparation Example 4 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one and potassium carbonate tetrahydrofuran solution: 16.05 g of 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one and 15.25 g of potassium carbonate were dissolved in 50 mL of tetrahydrofuran.
[0030] Preparation Example 5 6-Chloro-oxazolo[4,5-b]pyridin-2(3H)one and sodium carbonate tetrahydrofuran solution: 16.05 g of 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one and 11.7 g of sodium carbonate were dissolved in 50 mL of tetrahydrofuran. Example
[0031] Example 1 S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate: Add 3.50 g of 110 mmol of sulfur, 12.1 g of 110 mmol of dimethyl phosphite and 100 mL of tetrahydrofuran into the reactor, turn on the magnetic stirring device, add 5.95 g of 110 mml of sodium methoxide in batches under ice bath conditions, raise the temperature to 20°C after the addition, keep the temperature for 2 hours, monitor the residual amount of dimethyl phosphite (colored by potassium permanganate color developer) by thin layer chromatography until the reaction is complete; S2, O,O-dimethylthiophosphate reacts with bromoiodomethane to form S-(bromomethyl) O,O-dimethylthiophosphate; Under stirring conditions, the temperature was controlled at 20°C, and 110 mmol of bromoiodomethane (24.2 g) was added dropwise to the reaction solution obtained in S1. After the addition was completed, the reaction was continued at 20°C for 1 hour, and the reaction was terminated; S3, S-(bromomethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate: Under stirring conditions, the tetrahydrofuran solution of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and sodium methoxide obtained in Preparation Example 1 was added dropwise to the reaction solution obtained in S2. After the addition was completed, the mixture was kept warm for 2 hours. The residual amount of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one was monitored by thin layer chromatography. After the reaction was complete, the reaction was terminated. S4, purification of methyl pyridinium phos: The reaction solvent was evaporated from the reaction liquid obtained in S3, 40 ml of methanol was added, the temperature was raised to 40°C with stirring to completely dissolve, the insoluble matter was filtered out, the temperature was controlled at 40°C, 88 ml of water was added dropwise to the reaction liquid to precipitate crystals, which were filtered and dried to obtain methyl pyridinium phosphonate. The product was a white solid, and the one-pot total yield was 80.8%.
[0032] Example 2 S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate: Add 3.50 g of 110 mmol of sulfur, 12.1 g of 110 mmol of dimethyl phosphite and 100 mL of tetrahydrofuran into the reactor, turn on the magnetic stirring device, add 5.95 g of 110 mmol of sodium methoxide in batches under ice bath conditions, raise the temperature to 15°C after the addition, keep the temperature for 2 hours, monitor the residual amount of dimethyl phosphite (colored by potassium permanganate color developer) by thin layer chromatography until the reaction is complete; S2, O,O-dimethylthiophosphate reacts with bromoiodomethane to form S-(bromomethyl) O,O-dimethylthiophosphate; Under stirring conditions, the temperature was controlled at 10°C, and 110 mmol of bromoiodomethane (24.2 g) was added dropwise to the reaction solution obtained in S1. After the addition was completed, the reaction was continued at 15°C for 1 hour, and the reaction was terminated; S3, S-(bromomethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate: Under stirring conditions, the tetrahydrofuran solution of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and N,N-diisopropylethylamine obtained in Preparation Example 2 was added dropwise to the reaction solution obtained in S2. After the addition was completed, the mixture was kept warm for 2 hours. The residual amount of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one was monitored by thin layer chromatography. After the reaction was complete, the reaction was terminated. S4, purification of methyl pyridinium phos: The reaction solvent was evaporated from the reaction liquid obtained in S3, 40 ml of methanol was added, the temperature was raised to 35°C with stirring to completely dissolve, the insoluble matter was filtered out, the temperature was controlled at 35°C, 88 ml of water was added dropwise to the reaction liquid to precipitate crystals, which were filtered and dried to obtain methyl pyridinium phosphonate. The product was a white solid, and the one-pot total yield was 80.3%.
[0033] Example 3 S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate: Add 3.50 g of 110 mmol of sulfur, 12.1 g of 110 mmol of dimethyl phosphite and 100 mL of tetrahydrofuran into the reactor, turn on the magnetic stirring device, add 5.95 g of 110 mmol of sodium methoxide in batches under ice bath conditions, after the addition, heat to 25°C, keep the temperature for 2 hours, monitor the residual amount of dimethyl phosphite (colored by potassium permanganate color developer) by thin layer chromatography until the reaction is complete; S2, O,O-dimethylthiophosphate reacts with bromoiodomethane to form S-(bromomethyl) O,O-dimethylthiophosphate; Under stirring conditions, the temperature was controlled at 30°C, and 110 mmol of bromoiodomethane (24.2 g) was added dropwise to the reaction solution obtained in S1. After the addition was completed, the reaction was continued at 25°C for 1 hour, and the reaction was terminated; S3, S-(bromomethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate: Under stirring conditions, the tetrahydrofuran solution of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and sodium methoxide obtained in Preparation 3 was added dropwise to the reaction solution obtained in S2. After the addition was completed, the mixture was kept warm for 2 hours. The residual amount of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one was monitored by thin layer chromatography. After the reaction was complete, the reaction was terminated. S4, purification of methyl pyridinium phos: The reaction solvent was evaporated from the reaction liquid obtained in S3, 40 ml of methanol was added, the temperature was raised to 45°C with stirring to completely dissolve, the insoluble matter was filtered out, the temperature was controlled at 45°C, 88 ml of water was added dropwise to the reaction liquid to precipitate crystals, which were filtered and dried to obtain methyl pyridinium phosphonate. The product was a white solid, and the one-pot total yield was 80.5%.
[0034] Example 4 S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate: Add 3.50 g of 110 mmol of sulfur, 12.1 g of 110 mmol of dimethyl phosphite and 100 mL of tetrahydrofuran into the reactor, turn on the magnetic stirring device, add 5.95 g of 110 mmol of sodium methoxide in batches under ice bath conditions, after the addition, heat to 22°C, keep the temperature for 2 hours, monitor the residual amount of dimethyl phosphite (colored by potassium permanganate color developer) by thin layer chromatography until the reaction is complete; S2, O,O-dimethylthiophosphate reacts with chloroiodomethane to form S-(chloromethyl) O,O-dimethylthiophosphate; Under stirring conditions, the temperature was controlled at 22°C, and 19.4 g of 110 mmol of chloroiodomethane was added dropwise to the reaction solution obtained in S1. After the addition was completed, the reaction was continued at 22°C for 1 hour, and the reaction was terminated; S3, S-(chloromethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate: Under stirring conditions, the tetrahydrofuran solution of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and sodium methoxide obtained in Preparation Example 4 was added dropwise to the reaction solution obtained in S2. After the addition was completed, the mixture was kept warm for 2 hours. The residual amount of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one was monitored by thin layer chromatography. After the reaction was complete, the reaction was terminated. S4, purification of methyl pyridinium phos: The reaction solvent was evaporated from the reaction liquid obtained in S3, 40 ml of methanol was added, the temperature was raised to 42°C with stirring to completely dissolve, the insoluble matter was filtered out, the temperature was controlled at 42°C, 88 ml of water was added dropwise to the reaction liquid to precipitate crystals, which were filtered and dried to obtain methyl pyridinium phosphonate. The product was a white solid, and the one-pot total yield was 80.4%.
[0035] Example 5 S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate: Add 3.50 g of 110 mmol of sulfur, 12.1 g of 110 mmol of dimethyl phosphite and 100 mL of tetrahydrofuran into the reactor, turn on the magnetic stirring device, add 5.95 g of 110 mmol of sodium methoxide in batches under ice bath conditions, raise the temperature to 18°C after the addition, keep the temperature for 2 hours, monitor the residual amount of dimethyl phosphite (colored by potassium permanganate color developer) by thin layer chromatography until the reaction is complete; S2, O,O-dimethylthiophosphate reacts with chloroiodomethane to form S-(chloromethyl) O,O-dimethylthiophosphate; Under stirring conditions, the temperature was controlled at 18°C, and 19.4 g of 110 mmol of chloroiodomethane was added dropwise to the reaction solution obtained in S1. After the addition was completed, the reaction was continued at 18°C for 1 hour, and the reaction was terminated; S3, S-(chloromethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate: Under stirring conditions, the tetrahydrofuran solution of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and sodium methoxide obtained in Preparation Example 5 was added dropwise to the reaction solution obtained in S2. After the addition was completed, the mixture was kept warm for 2 hours. The residual amount of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one was monitored by thin layer chromatography. After the reaction was complete, the reaction was terminated. S4, purification of methyl pyridinium phos: The reaction solvent was evaporated from the reaction liquid obtained in S3, 40 ml of methanol was added, the temperature was raised to 38°C with stirring to completely dissolve, the insoluble matter was filtered out, the temperature was controlled at 38°C, 88 ml of water was added dropwise to the reaction liquid to precipitate crystals, which were filtered and dried to obtain methyl pyridinium phosphonate. The product was a white solid, and the one-pot total yield was 80.2%.
[0036] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.
Claims
1. A method for preparing methyl pyridinium phosphine by a one-pot process, characterized in that: The steps include: S1, sulfur and dimethyl phosphite react to form O,O-dimethylthiophosphate; S2, O,O-dimethylthiophosphate reacts with bromoiodomethane or chloroiodomethane to form S-(halomethyl) O,O-dimethylthiophosphate, the structural formula is X=Br or Cl; S3, S-(halomethyl) O,O-dimethyl phosphorothioate and 6-chloro-oxazolo[4,5-b]pyridin-2(3H)one react to form methyl pyridinium phosphonate.
2. The method for preparing methyl pyridinium phosphine by one-pot method according to claim 1, characterized in that: The steps include: S1, add sulfur, dimethyl phosphite and tetrahydrofuran as solvent into the reactor, start stirring, cool to -3-3°C, add sodium methoxide in batches, raise the temperature to 15-25°C, and keep the temperature to react until the end; the reaction formula is as follows: S2, control the temperature at 10-30°C, add bromoiodomethane or chloroiodomethane dropwise to the reaction solution obtained in S1, and after the addition is complete, continue the reaction at room temperature until completion; the reaction formula is as follows, wherein X is Cl or Br: S3, add 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and a tetrahydrofuran solution of a base to the reaction solution obtained in S2, and after the addition is complete, continue to heat and react until the reaction is complete; the reaction formula is as follows: S4, evaporating the reaction solvent from the reaction solution obtained in S3, adding methanol, stirring and heating to 35-45°C to dissolve, filtering out insoluble matter, controlling the temperature to 35-45°C, adding water dropwise to precipitate crystals, filtering and drying to obtain methyl pyridinium phosphide.
3. The method for preparing methyl pyridinium phosphide by a one-pot process according to claim 2, characterized in that: In S1, after adding sodium methoxide, the residual amount of dimethyl phosphite is monitored by thin layer chromatography to determine the end of the reaction.
4. The method for preparing methyl pyridinium phosphide in one pot according to claim 2, characterized in that: In step S3, after the dropwise addition of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one and the tetrahydrofuran solution of the base is completed, thin layer chromatography is used to monitor the complete reaction of 6-chloro-oxazolo[4,5-b]pyridine-2(3H)one, and the reaction is terminated.
5. The method for preparing methyl pyridinium phosphine by one-pot method according to claim 2, characterized in that: The base in S3 is one of sodium methoxide, N,N-diisopropylethylamine, triethylamine, potassium carbonate and sodium carbonate.
6. The method for preparing methyl pyridinium phosphat by one-pot method according to claim 2, characterized in that: The molar ratio of sodium methoxide, sulfur and dimethyl phosphite in S1 is 1:1:1.