A method for synthesizing acephate

Abstract

The invention belongs to the field of pesticide chemicals, and in particular to a kind of synthetic method of acephate. Phosphorus oxychloride and methanol generate methyl dichlorophosphate through substitution reaction, methyl dichlorophosphate and ammonia generate methylphosphoramide chloride through acylation reaction, methylphosphoramide chloride and methyl mercaptan obtain methylamidophos through substitution reaction, and methylamidophos and acetic anhydride generate acephate through acylation reaction. Using phosphorus oxychloride as raw material, by multiple substitution reactions and one-step acylation reaction, target product can be obtained, avoiding the reaction of phosphorus trichloride and sulfur under high temperature conditions and the isomerization reaction of O, O-dimethylthiophosphoramide, and the use of caustic alkali. Meanwhile, the product appearance properties prepared by the inventive method are good.

Description

Technical Field

[0001] The invention belongs to the field of pesticide chemicals, and particularly relates to a method for synthesizing acephate. Background Art

[0002] Acephate is an acylated derivative of the insecticide methamidophos. It is a highly effective, low-toxic, low-residue broad-spectrum insecticide. There are several synthesis methods for acephate:

[0003]

[0004] The method uses a highly toxic raw material, methylaminophos, and also uses dangerous reagents, such as ketene, which has a boiling point of -56°C and is extremely unstable. It needs to be stored at a low temperature of -80°C. It polymerizes into diketene at room temperature, which is highly toxic and explosive. The reaction conditions are harsh, such as requiring a vacuum of -0.08 to -0.1 MPa; the solvents used are special, such as aliphatic carboxylic acid esters, C2-C12 carboxylic acid C1 to C8 esters; the instruments and equipment are expensive, and specially customized instruments are required.

[0005]

[0006] Using spermine as the raw material, the reaction produces many by-products and also uses hazardous reagents. Dimethyl sulfate is highly toxic, with acute toxicity similar to phosgene, and is a potential carcinogen and mutagen. The reaction conditions are harsh, and the reaction needs to be maintained at 50-120°C for a long time. High requirements are placed on instruments and equipment, including advanced flow reactors (AFRs), rotating disk reactors (SDRs), moving bed reactors (MBRs), loop reactors, and other equipment.

[0007]

[0008] Acetylspermine is one of the by-products of the preparation of acephate from spermine, so it is difficult to obtain and has a high price, making it unsuitable for actual production needs; and the reaction needs to be carried out in an inert gas atmosphere at a pressure of 50-120 MPa and a temperature of 30-80°C.

[0009]

[0010] O,O,O-trimethylmercaptophosphate is used as raw material, and the highly toxic gas phosgene and solvent toluene are applied, which places high demands on production equipment and personnel, thereby increasing labor costs; the reaction produces the highly toxic substance methyl chloroformate, which is difficult to store and handle; the production process of the product is highly harmful to human health and the ecological environment.

[0011]

[0012] Highly toxic phosphorus trichloride is used as raw material, and dangerous reagents are applied. Dimethyl sulfate is highly toxic, with acute toxicity similar to phosgene, and is a potential carcinogen and mutagen. The reagents are expensive and produce many by-products, which increases production costs, environmental protection costs, and the difficulty of governance. Summary of the Invention

[0013] In order to solve the technical problems pointed out in the background technology section, the present invention provides a method for synthesizing acephate, wherein phosphorus oxychloride is used as a raw material, and is reacted with methanol to generate methyl dichlorophosphate (2), (2) is reacted with ammonia to generate methylphosphoramide chloride (3), (3) is reacted with methyl mercaptan to generate acephate (4), and (4) is reacted with acetic anhydride to generate the final product acephate (1).

[0014]

[0015] Formula 1 Synthesis route of acephate

[0016] The specific synthesis steps are as follows:

[0017] (1) Synthesis of Compound 2

[0018] Phosphorus oxychloride was added to a round-bottom flask, followed by dissolution in anhydrous tetrahydrofuran. Chromatographic-grade anhydrous methanol was added dropwise under an ice bath. After completion of the addition, the mixture was allowed to react at room temperature. After 3 hours, TLC confirmed the reaction was complete. The anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to obtain compound 2, methyl dichlorophosphate, as a yellow oil, which was directly used in the next reaction.

[0019] The molar ratio of phosphorus oxychloride to methanol is 1:1.0-1.5, and the dripping rate of methanol is 1 d / s.

[0020] (2) Synthesis of compound 3

[0021] Compound 2 was added to a round-bottom flask and dissolved in anhydrous tetrahydrofuran. A 0.40 mol / L ammonia solution in dioxane was added dropwise under an ice bath. After completion of the addition, the mixture was allowed to react at room temperature. After 3 hours, TLC confirmed that the starting material had essentially reacted. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness, yielding 3-methylphosphoramidite chloride as a yellow oil, which was used directly in the next reaction.

[0022] The molar ratio of compound 2 to ammonia is 1:1.0-1.5, and the dripping rate of the ammonia-dioxane solution is 1 d / s.

[0023] (3) Synthesis of compound 4

[0024] Compound 3 was added to a round-bottom flask and dissolved in anhydrous tetrahydrofuran. Excess methyl mercaptan gas was introduced into the solution and stirred at room temperature. After 0.5 h, the reaction was complete as determined by TLC. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to obtain compound 4-methylphosphonium amine as a yellow oil.

[0025] (4) Synthesis of acephate

[0026] Compound 4 was placed in a round-bottom flask, and acetic anhydride, dimethyl sulfide, and 98% concentrated sulfuric acid were added in sequence. The mixture was stirred at 65°C and the reaction was complete after 3 hours by TLC. Aqueous ammonia was slowly added dropwise to neutralize the acetic acid generated during the reaction, adjusting the pH to 7-8. Chloroform was then added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain compound 1 as a yellow oil.

[0027] The molar ratio of compound 4, acetic anhydride, 98% concentrated sulfuric acid, and dimethyl sulfide is 1:1.0-1.5:0.0075:0.05.

[0028] Beneficial effects:

[0029] The invention adopts phosphorus oxychloride as a raw material to generate an intermediate, and the product yield obtained through substitution and acylation reaction is high. The reaction conditions are mild, the equipment requirements are not high, the energy consumption is low, and the post-processing is simple. The invention has important significance for the diversified synthesis and production of acephate.

[0030] The method of the present invention can react at room temperature, avoiding the reaction of phosphorus trichloride and sulfur at high temperature (100°C).

[0031] The use of caustic soda, dimethyl sulfate, and toluene in the isomerization reaction of O,O-dimethylthiophosphoramide (spermine) and the like also avoids problems such as insufficient conversion and intermediate loss during the isomerization process. Furthermore, the product prepared by this method exhibits excellent appearance. DETAILED DESCRIPTION

[0032] The present invention is described in detail below with reference to specific embodiments.

[0033] Example 1

[0034] (1) Synthesis of 2

[0035] Phosphorus oxychloride (1.00 g, 6.52 mmol) was added to a 100 mL round-bottom flask, followed by dissolution in 20 mL of anhydrous tetrahydrofuran. 208.91 mg of chromatographic-grade anhydrous methanol was added dropwise under an ice bath at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed the reaction was complete. The anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness, yielding 20.91 g of the compound as a yellow oil (93.73% yield), which was used directly in the next step.

[0036] (2) Synthesis of 3

[0037] To a 100 mL round-bottom flask, 2 (0.91 g, 6.11 mmol) was added and dissolved in 20 mL of anhydrous tetrahydrofuran. Under an ice bath, 15.27 mL of a 0.40 mol / L ammonia solution in dioxane was added dropwise at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed that the starting material had essentially reacted. The resulting white solid was filtered and evaporated to dryness in anhydrous tetrahydrofuran under reduced pressure to afford 0.75 g of compound 3 as a yellow oil (95.18% yield), which was used directly in the next reaction.

[0038] (3) Synthesis of 4

[0039] 3 (0.75 g, 5.82 mmol) was added to a 100 mL round-bottom flask and dissolved in 20 mL of anhydrous tetrahydrofuran. Methyl mercaptan gas (excess) was introduced into the solution and stirred at room temperature. After 0.5 h, TLC confirmed the reaction was complete. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to afford 0.80 g of compound 4 as a yellow oil in a 97.40% yield.

[0040] (4) Synthesis of acephate

[0041] Compound 4 (800 mg, 5.67 mmol) was placed in a 100 mL round-bottom flask, and acetic anhydride (636.36 mg, 6.24 mmol), dimethyl sulfide (2.49 mg, 0.04 mmol), and 98% concentrated sulfuric acid (27.46 mg, 0.28 mmol) were added sequentially. The mixture was stirred at 65°C. After 3 h, the reaction was complete as determined by TLC. Aqueous ammonia was slowly added dropwise to neutralize the acetic acid generated during the reaction, adjusting the pH to 7-8. Chloroform was then added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 987.23 mg of compound 1 as a yellow oil in a yield of 95.00%. 1 H NMR (400MHz, Chloroform-d) δ4.03(s,3H),1.99(s,3H),1.64(s,3H).

[0042] Example 2

[0043] (1) Synthesis of 2

[0044] Phosphorus oxychloride (1.00 g, 6.52 mmol) was added to a 100 mL round-bottom flask, followed by dissolution in 20 mL of anhydrous tetrahydrofuran. 250.55 mg of chromatographic-grade anhydrous methanol was added dropwise under an ice bath at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed the reaction was complete. The anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness, yielding 20.87 g of the compound as a yellow oil (89.61% yield), which was used directly in the next step.

[0045] (2) Synthesis of 3

[0046] To a 100 mL round-bottom flask, 2 (0.87 g, 5.84 mmol) was added and dissolved in 20 mL of anhydrous tetrahydrofuran. Under an ice bath, 17.52 mL of a 0.40 mol / L ammonia solution in dioxane was added dropwise at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed that the starting material had essentially reacted. The resulting white solid was filtered and evaporated to dryness in anhydrous tetrahydrofuran under reduced pressure to afford 0.69 g of compound 3 as a yellow oil (91.25% yield), which was used directly in the next reaction.

[0047] (3) Synthesis of 4

[0048] 3 (0.69 g, 5.33 mmol) was added to a 100 mL round-bottom flask and dissolved in 20 mL of anhydrous tetrahydrofuran. Methyl mercaptan gas (excess) was introduced into the solution and stirred at room temperature. After 0.5 h, TLC confirmed the reaction was complete. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to afford 0.73 g of compound 4 as a yellow oil in a 97.06% yield.

[0049] (4) Synthesis of acephate

[0050] 4 (730 mg, 5.17 mmol) was placed in a 100 mL round-bottom flask, and acetic anhydride (632.96 mg, 6.20 mmol), dimethyl sulfide (2.49 mg, 0.04 mmol), and 98% concentrated sulfuric acid (25.50 mg, 0.26 mmol) were added sequentially. The mixture was stirred at 65°C. After 3 h, the reaction was complete as determined by TLC. Aqueous ammonia was slowly added dropwise to neutralize the acetic acid generated during the reaction, adjusting the pH to 7-8. Chloroform was then added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 888.33 mg of compound 1 as a yellow oil in a yield of 93.81%. 1H NMR (400MHz, Chloroform-d) δ4.03(s,3H),1.99(s,3H),1.64(s,3H).

[0051] Example 3

[0052] (1) Synthesis of 2

[0053] Phosphorus oxychloride (1.00 g, 6.52 mmol) was added to a 100 mL round-bottom flask, followed by dissolution in 20 mL of anhydrous tetrahydrofuran. 313.37 mg of chromatographic-grade anhydrous methanol was added dropwise under an ice bath at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed the reaction was complete. The anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness, yielding 20.81 g of the compound as a yellow oil (83.43% yield), which was used directly in the next reaction.

[0054] (2) Synthesis of 3

[0055] To a 100 mL round-bottom flask, 2 (0.81 g, 5.44 mmol) was added and dissolved in 20 mL of anhydrous tetrahydrofuran. Under an ice bath, 20.40 mL of a 0.40 mol / L ammonia solution in dioxane was added dropwise at a rate of 1 d / s. After completion of the addition, the mixture was allowed to react at room temperature. After 3 h, TLC confirmed that the starting material had essentially reacted. The resulting white solid was filtered and evaporated to dryness in anhydrous tetrahydrofuran under reduced pressure to afford 0.59 g of compound 3 as a yellow oil (83.76% yield), which was used directly in the next step.

[0056] (3) Synthesis of 4

[0057] 3 (0.59 g, 4.56 mmol) was added to a 100 mL round-bottom flask and dissolved in 20 mL of anhydrous tetrahydrofuran. Methyl mercaptan gas (excess) was introduced into the solution and stirred at room temperature. After 0.5 h, TLC confirmed the reaction was complete. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to afford 0.62 g of compound 4 as a yellow oil in a 96.35% yield.

[0058] (4) Synthesis of acephate

[0059] 4 (620 mg, 4.39 mmol) was placed in a 100 mL round-bottom flask, and acetic anhydride (672.77 mg, 6.59 mmol), dimethyl sulfide (1.86 mg, 0.03 mmol), and 98% concentrated sulfuric acid (21.58 mg, 0.22 mmol) were added sequentially. The mixture was stirred at 65°C. After 3 h, the reaction was complete as determined by TLC. Aqueous ammonia was slowly added dropwise to neutralize the acetic acid generated during the reaction, adjusting the pH to 7-8. Chloroform was then added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 739.97 mg of compound 1 as a yellow oil in a yield of 92.03%. 1 H NMR (400MHz, Chloroform-d) δ4.03(s,3H),1.99(s,3H),1.64(s,3H).

[0060] Example 4

[0061] (1) Synthesis of 2

[0062] Phosphorus oxychloride (1.00 g, 6.52 mmol) was added to a 100 mL round-bottom flask, followed by dissolution in 20 mL of anhydrous tetrahydrofuran. 208.91 mg of chromatographic-grade anhydrous methanol was added dropwise at 0°C at a rate of 1 d / s. After the addition was complete, the reaction was stirred at 0°C. After 5 h, TLC confirmed the reaction was complete. The anhydrous tetrahydrofuran was evaporated to dryness under reduced pressure to afford 0.88 g of compound 2 as a yellow oil (90.72% yield), which was used directly in the next reaction.

[0063] (2) Synthesis of 3

[0064] To a 100 mL round-bottom flask, 2 (0.88 g, 5.91 mmol) was added and dissolved in 20 mL of anhydrous tetrahydrofuran. 14.78 mL of a 0.40 mol / L ammonia solution in dioxane was added dropwise at 0°C at a rate of 1 d / s. After the addition was complete, the reaction was stirred at 0°C. After 5 h, TLC confirmed that the starting material had essentially reacted. The resulting white solid was filtered and evaporated to dryness in anhydrous tetrahydrofuran under reduced pressure to afford 0.71 g of compound 3 as a yellow oil (92.78% yield), which was used directly in the next step.

[0065] (3) Synthesis of 4

[0066] 3 (0.71 g, 5.48 mmol) was added to a 100 mL round-bottom flask and dissolved in 20 mL of anhydrous tetrahydrofuran. Methyl mercaptan gas (excess) was introduced into the solution, and the reaction was stirred at 0°C. After 1.5 h, TLC confirmed the reaction was complete. The resulting white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness, affording 0.70 g of compound 4 as a yellow oil in a 90.52% yield.

[0067] (4) Synthesis of acephate

[0068] 4 (0.70 g, 4.96 mmol) was placed in a 100 mL round-bottom flask, and acetic anhydride (0.56 g, 5.46 mmol), dimethyl sulfide (2.49 mg, 0.04 mmol), and 98% concentrated sulfuric acid (24.52 mg, 0.25 mmol) were added in sequence. The mixture was stirred at 70°C. After 2.5 h, the reaction was complete as determined by TLC. Aqueous ammonia was slowly added dropwise to neutralize the acetic acid generated during the reaction, adjusting the pH to 7-8. Chloroform was then added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 0.86 g of compound 1 as a yellow oil with a yield of 94.66%. 1 H NMR (400MHz, Chloroform-d) δ4.03(s,3H),1.99(s,3H),1.64(s,3H).

Claims

1. A method for synthesizing acephate, characterized in that: The synthesis method steps are as follows: (1) Synthesis of methyl dichlorophosphate Phosphorus oxychloride was added to a round-bottom flask, followed by dissolution in anhydrous tetrahydrofuran. Anhydrous methanol was then added dropwise under an ice bath. After the addition was complete, the mixture was allowed to react at room temperature for 3-5 hours. After TLC analysis, the reaction was complete. The anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to obtain methyl dichlorophosphate as a yellow oily liquid. (2) Synthesis of methylphosphoramide chloride Add methyl dichlorophosphate to a round-bottom flask and dissolve it in anhydrous tetrahydrofuran. Add a 0.40 mol / L ammonia solution in dioxane dropwise in an ice bath. After the addition is complete, move to room temperature and react for 3-5 hours. After TLC, the reaction is complete. Filter the resulting white solid and evaporate the anhydrous tetrahydrofuran under reduced pressure to dryness to obtain methylphosphoramidite chloride as a yellow oil. The molar ratio of methyl dichlorophosphate to ammonia is 1:1.0-1.5, and the dripping rate of the ammonia dioxane solution is 1 d / s; (3) Synthesis of methamidophos Methylphosphoramide chloride was added to a round-bottom flask and dissolved in anhydrous tetrahydrofuran. Excess methyl mercaptan gas was introduced into the solution and stirred at room temperature. After 0.5-1.5 h, the reaction was completed by TLC detection. The generated white solid was filtered and the anhydrous tetrahydrofuran was evaporated under reduced pressure to dryness to obtain methylphosphoramidophos as a yellow oily liquid. (4) Synthesis of acephate Methamidophos was placed in a round-bottom flask, and acetic anhydride, dimethyl sulfide, and 98% concentrated sulfuric acid were added in sequence. The mixture was stirred at 65-70°C. After 2.5-3 hours, TLC was performed to check the reaction completion. Ammonia was added dropwise to adjust the pH value, and chloroform was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by column chromatography to obtain a yellow oily compound, acephate. The molar ratio of methamidophos, acetic anhydride, 98% concentrated sulfuric acid, and dimethyl sulfide is 1:1.0-1.5:0.0075:0.

05.

2. The synthetic method of acephate as claimed in claim 1, wherein: In step (1), the molar ratio of phosphorus oxychloride to methanol is 1:1.0-1.5, and the dripping rate of methanol is 1 d / s.

3. The synthetic method of acephate as claimed in claim 1, wherein: In step (4), aqueous ammonia is added dropwise to adjust the pH value to 7-8 to neutralize the acetic acid generated in the reaction.

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