Preparation method and application of methyl 3,3-dialkoxypropylmethylphosphonate

Abstract

The invention discloses the preparation method and application of 3,3-dialkoxypropylmethylphosphonic acid methyl ester, a key intermediate of glufosinate ammonium. The preparation method of the present invention is to use dimethoxyphosphorus chloride as a raw material, react with a Grignard reagent (1-halogenated-3,3-dialkoxypropane and magnesium to make it) or with a Turbo Grignard reagent (1-halogenated-3,3-dialkoxypropane and magnesium and auxiliary agent lithium chloride to make it) (also known as a Konchel type Grignard reagent), and then react with Arbuzov rearrangement reaction under the action of a catalyst to obtain 3,3-dialkoxypropylmethylphosphonic acid methyl ester. The reaction raw materials used in the synthesis method are simple and easy to obtain, the reaction conditions are easy to control, the by-products generated by the reaction are few, the reaction yield is high, the "three wastes" are less green and environmentally friendly, and the process is feasible by amplification verification.

Description

Technical Field

[0001] The invention relates to a preparation method and application of 3,3-dialkoxypropylmethylphosphonic acid methyl ester, and belongs to the fields of organic synthetic chemistry and pesticide chemistry. Background Art

[0002] Glufosinate is a broad-spectrum contact-killing organophosphorus herbicide that inhibits the production of glutamine synthetase (GS) in plants, interrupts the reversible reaction of glutamate in plants, causes ammonia accumulation, and thus leads to plant death. The molecular structure of glufosinate contains a chiral carbon atom and is optically active. Common glufosinate is a mixture of racemates. Its chemical name is 4-[hydroxy(methyl)phosphonyl]-DL-homoalanine monoammonium salt, and its chemical formula is C5H 15 N2O4P, CAS registration number 77182-82-2, is a light yellow to white powdery crystal with the advantages of fast weed control, wide range of action, low toxicity, harmlessness and easy degradation.

[0003] Following the ban on paraquat, glufosinate has become one of the world's largest tonnage herbicides, second only to glyphosate in the tolerance of genetically modified crops. With the spread of glyphosate-resistant weeds, the market demand for glufosinate is even more obvious. On the other hand, glufosinate is the only approved genetically modified rice tolerance herbicide. Once glufosinate-resistant genetically modified crops are widely planted and used around the world, glufosinate will have a broader market.

[0004] The Strecker synthesis method is currently a common method for the industrial production of glufosinate-ammonium, and its synthesis route is as follows:

[0005]

[0006] Among them, 3,3-dialkoxypropyl methylphosphonate is a key intermediate of the Strecker route. CN109134534A reports a simple preparation method of 3,3-dialkoxypropyl methylphosphonate: 3,3-dialkoxypropyl methylphosphonate is obtained by reacting methyl halophosphonic acid monoester with 3,3-dialkoxypropyl magnesium halide or zinc halide. The reaction formula is as follows:

[0007]

[0008] However, in this method, the raw material methyl (methoxy)phosphonyl chloride is prepared by reacting dimethyl methylphosphonate (DMMP) with solid phosgene or phosphorus pentachloride. The reaction is exothermic and violent, and the feed rate and temperature need to be strictly controlled. The risk factor is high, and the production cost is high. The by-products are difficult to separate and polymers are easily generated. Therefore, the safety factor and synthesis cost are high, and it is not easy to industrialize production. Summary of the invention

[0009] Purpose of the invention: The first purpose of the present invention is to provide a method for preparing 3,3-dialkoxypropylmethylphosphonic acid methyl ester; the second purpose of the present invention is to provide the application of the key intermediate of 3,3-dialkoxypropylmethylphosphonic acid methyl ester in the preparation of glufosinate ammonium.

[0010] Technical solution: The preparation method of methyl 3,3-dialkoxypropyl methylphosphonate of the present invention is as follows: the methyl 3,3-dialkoxypropyl methylphosphonate is prepared by reacting dimethoxyphosphonium chloride with a Grignard reagent or a Turbo Grignard reagent (also known as a Konchel-type Grignard reagent), and then undergoing Arbuzov rearrangement under the action of a catalyst. The synthesis route is as follows:

[0011]

[0012] Wherein, X is selected from Cl, Br, I; R1 is a C1-C5 straight chain alkyl or a branched alkyl or two R1 are methylene -(CH2) n -form is connected to oxygen atoms to form a 3- to 6-membered ring structure, with n being 2 or 3.

[0013] Wherein, the Grignard reagent is a Grignard reagent obtained by reacting 1-halogenated-3,3-dialkoxypropane with metal magnesium.

[0014] The Turbo Grignard reagent is a Turbo Grignard reagent obtained by reacting 1-halogenated-3,3-dialkoxypropane with metal magnesium and auxiliary agent lithium chloride.

[0015] Wherein, the 3-6-membered cyclic structure is a cyclic acetal structure or a branched cyclic acetal structure.

[0016] The preparation method of methyl 3,3-dialkoxypropyl methylphosphonate of the present invention comprises the following steps:

[0017] (1) 1-halogenated-3,3-dialkoxypropane reacts with magnesium metal to obtain a Grignard reagent, or lithium chloride is added as an auxiliary agent to obtain a Turbo Grignard reagent, which is then reacted with dimethoxyphosphorus chloride to obtain an intermediate product;

[0018] (2) Adding or not adding a catalyst to the intermediate product to obtain 3,3-dialkoxypropylmethylphosphonic acid methyl ester through Arbuzov rearrangement reaction.

[0019] Wherein, in step (1), the temperature for the reaction of the Grignard reagent or Turbo Grignard reagent with dimethoxyphosphorus chloride is -50°C to 120°C, and the reaction time is 0.5 to 48 hours.

[0020] Wherein in step (1), when preparing the Grignard reagent, the molar ratio of the 1-halogenated-3,3-dialkoxypropane to the magnesium metal is 1:1-6.

[0021] Wherein, when preparing the Turbo Grignard reagent, the molar ratio of the 1-halogenated-3,3-dialkoxypropane to the metal magnesium and lithium chloride is 1:1-6:0.05-15.

[0022] Wherein, in step (1), the molar ratio of dimethoxyphosphorus chloride to Grignard reagent or Turbo Grignard reagent is 1:0.5-5.

[0023] Wherein, in step (2), the temperature of the reaction of the intermediate product through Arbuzov rearrangement is 0°C to 220°C, and the reaction time is 0.5 to 48 hours.

[0024] Wherein, in step (2), one or more of methyl chloride, methyl iodide, dimethyl carbonate, trimethyl phosphate, dimethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, methyl formate, and trimethyl orthoformate may be added to carry out the catalytic reaction during the Arbuzov rearrangement reaction.

[0025] In which, an organic solvent is used as a reaction solvent during the preparation process, and the organic solvent is tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, cyclohexane, decahydronaphthalene, toluene, xylene, trimethylbenzene, ether, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N-methylpyrrolidone or dimethyl sulfoxide.

[0026] The present invention also includes the use of the 3,3-dialkoxypropylmethylphosphonic acid methyl ester intermediate obtained by the preparation method in the preparation of the herbicide glufosinate ammonium.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0028] Dimethoxyphosphorus chloride can be prepared from phosphorus trichloride and trimethyl phosphite. The entire 3,3-dialkoxypropylmethylphosphonic acid methyl ester intermediate preparation process is simple and easy, with low production cost, stable reaction, no large amount of heat release, high safety factor, less three wastes, high reaction conversion rate and yield, and few side reactions. It is a feasible industrial preparation route. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The hydrogen nuclear magnetic resonance spectrum of 3,3-dimethoxypropylmethylphosphonic acid methyl ester prepared in Example 1 ( 1 H-NMR); DETAILED DESCRIPTION

[0030] The technical solution of the present invention is further described below in conjunction with the accompanying drawings.

[0031] Example 1

[0032] (1) Preparation of 3,3-dimethoxypropylmagnesium chloride

[0033] Under nitrogen protection, add 133g (5.542mol) of magnesium chips and 400mL of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, heat to 70°C, add 1mL of 1,2-dibromoethane under reflux to initiate, then cool to room temperature, slowly add 2.1L of anhydrous tetrahydrofuran solution containing 690g (4.979mol) of 1-chloro-3,3-dimethoxypropane, and after the addition is complete, keep warm at 45°C for 2h to obtain a tetrahydrofuran solution of 3,3-dimethoxypropylmagnesium chloride.

[0034] (2) Preparation of dimethyl 3,3-dimethoxypropylphosphite

[0035] Under nitrogen protection, add 512g (3.985mol) of dimethoxyphosphorus chloride and 1.5L of anhydrous tetrahydrofuran to a 3L four-necked flask, stir evenly, cool to -35°C, slowly drop the tetrahydrofuran solution of 3,3-dimethoxypropylmagnesium chloride prepared in the above experiment, keep warm at 10°C for 8h. Reduce pressure and rotary concentrate to remove the solvent and recover tetrahydrofuran; add 200mL of dichloroethane to the reaction solution at 0°C, pass 4-5mol of anhydrous hydrogen chloride gas, filter and recover solid magnesium chloride, and reduce pressure and rotary concentrate to obtain 703g of crude 3,3-dimethoxypropylphosphinate dimethyl ester.

[0036] (3) Preparation of 3,3-dimethoxypropylmethylphosphonate

[0037] In a 2L single-mouth bottle, add 703g of the prepared dimethyl 3,3-dimethoxypropylphosphinate, 15g of methyl p-toluenesulfonate, and 1.1L of xylene, stir evenly, heat to 120-150°C, react for 2h, and distill under reduced pressure to obtain 618g of methyl 3,3-dimethoxypropyl methylphosphonate with a GC purity of 98% and a yield of 79%.

[0038] The 3,3-dimethoxypropylmethylphosphonic acid methyl ester prepared in this example was subjected to nuclear magnetic resonance hydrogen spectrum analysis. The results are as follows: Figure 1 As shown, Figure 1 The hydrogen nuclear magnetic resonance spectrum of 3,3-dimethoxypropylmethylphosphonic acid methyl ester prepared in Example 1 ( 1 H-NMR).

[0039] Example 2

[0040] (1) Preparation of 3,3-dimethoxypropylmagnesium chloride (Turbo Grignard reagent)

[0041] Under nitrogen protection, add 133g (5.542mol) of magnesium chips, 10.77g (0.249mol) of 98% anhydrous lithium chloride and 400mL of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, heat to 55°C, add 1mL of 1,2-dibromoethane under reflux to initiate, then cool to room temperature, slowly add 2.1L of anhydrous tetrahydrofuran solution containing 690g (4.979mol) of 1-chloro-3,3-dimethoxypropane, and after the addition is complete, keep warm at 35°C for 2h to obtain a tetrahydrofuran solution of 3,3-dimethoxypropylmagnesium chloride.

[0042] (2) Preparation of dimethyl 3,3-dimethoxypropylphosphite

[0043] Under nitrogen protection, add 512g (3.985mol) of dimethoxyphosphorus chloride and 1.5L of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, cool to -35°C, slowly drop the tetrahydrofuran solution of 3,3-dimethoxypropylmagnesium chloride prepared in the above experiment, keep warm at 10°C for 8h. Concentrate under reduced pressure to remove the solvent, recover tetrahydrofuran, slowly drop saturated ammonium chloride solution (540g ammonium chloride / 1.6L water) at 0°C to quench, filter and recover 481g of solid magnesium chloride, add dichloroethane (200mL×3 times) to the filtrate to extract and separate, combine the organic phases, and recycle and concentrate under reduced pressure to recover dichloroethane to obtain 719g of dimethyl 3,3-dimethoxypropylphosphinate.

[0044] (3) Preparation of 3,3-dimethoxypropylmethylphosphonate

[0045] In a 2L single-necked bottle, add 719g of the prepared dimethyl 3,3-dimethoxypropylphosphinate, 16g of dimethyl carbonate, and 1L of toluene, stir evenly, heat to 120°C, react for 2h, and distill under reduced pressure to obtain 611g of methyl 3,3-dimethoxypropyl methylphosphonate with a GC purity of 98% and a yield of 78%.

[0046] Example 3

[0047] (1) Preparation of 3,3-dimethoxypropylmagnesium chloride (Turbo Grignard reagent)

[0048] Under nitrogen protection, 179.3 g (7.469 mol) of magnesium powder, 10.77 g (0.249 mol) of 98% anhydrous lithium chloride and 300 mL of anhydrous diethylene glycol dimethyl ether were added to a 3L four-necked bottle, stirred evenly, heated to 100°C, 1 mL of 1,2-dibromoethane was added to initiate, then cooled to room temperature, and 1.5 L of anhydrous diethylene glycol dimethyl ether solution containing 690 g (4.979 mol) of 1-chloro-3,3-dimethoxypropane was slowly added dropwise. After the addition was completed, the mixture was kept at 40°C for 2 h to obtain a diethylene glycol dimethyl ether solution of 3,3-dimethoxypropyl magnesium chloride.

[0049] (2) Preparation of dimethyl 3,3-dimethoxypropylphosphite

[0050] Under nitrogen protection, add 512g (3.985mol) of dimethoxyphosphorus chloride and 1L of anhydrous diethylene glycol dimethyl ether to a 3L four-necked flask, stir evenly, cool to -20°C, slowly drop the diethylene glycol dimethyl ether solution of 3,3-dimethoxypropyl zinc chloride prepared in the above experiment, keep warm at 30°C for 10h. Concentrate under reduced pressure to remove the solvent, recover diethylene glycol dimethyl ether, slowly drop saturated ammonium chloride solution (540g ammonium chloride / 1.6L water) at 0°C to quench, filter and recover 680g of solid zinc chloride, add dichloroethane (200mL×3 times) to the filtrate for extraction and stratification, combine the organic phases, and concentrate under reduced pressure to recover dichloroethane to obtain 664.5g of 3,3-dimethoxypropyl dimethyl phosphite.

[0051] (3) Preparation of 3,3-dimethoxypropylmethylphosphonate

[0052] Add 664.5 g of the prepared 3,3-dimethoxypropyl dimethyl phosphite, trimethyl phosphate, and 1 L of diethylene glycol dimethyl ether into a 2 L single-mouth bottle, stir evenly, heat to 120 ° C, react for 3 h, and distill under reduced pressure to obtain 528 g of 3,3-dimethoxypropyl methylphosphonate with GC purity of 98% and a yield of 67%.

[0053] Example 4

[0054] (1) Preparation of 3,3-diethoxypropylmagnesium chloride (Turbo Grignard reagent)

[0055] Under nitrogen protection, add 133g (5.542mol) of magnesium chips, 21.1g (0.498mol) of 98% anhydrous lithium chloride and 400mL of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, heat to 55°C, add 1mL of 1,2-dibromoethane under reflux to initiate, then cool to room temperature, slowly add 2.5L of anhydrous tetrahydrofuran solution containing 830g (4.979mol) of 1-chloro-3,3-diethoxypropane, and after the addition is complete, keep warm at 40°C for 2h to obtain a tetrahydrofuran solution of 3,3-diethoxypropylmagnesium chloride.

[0056] (2) Preparation of dimethyl 3,3-diethoxypropylphosphite

[0057] Under nitrogen protection, add 512g (3.985mol) of dimethoxyphosphorus chloride and 1.5L of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, cool to -25°C, slowly drop the tetrahydrofuran solution of 3,3-diethoxypropylmagnesium chloride prepared in the above experiment, keep at 20°C for 12h after the dropwise addition. Concentrate under reduced pressure to remove the solvent, recover tetrahydrofuran, slowly drop saturated ammonium chloride solution (540g ammonium chloride / 1.6L water) at 0°C to quench, filter and recover 481g of solid magnesium chloride, add dichloroethane (0.2mL×3 times) to the filtrate to extract and layer, combine the organic phases, and concentrate under reduced pressure to recover dichloroethane to obtain 786g of 3,3-diethoxypropylphosphinate dimethyl ester.

[0058] (3) Preparation of 3,3-diethoxypropylmethylphosphonic acid methyl ester

[0059] In a 2L single-mouth bottle, add 786g of the prepared dimethyl 3,3-diethoxypropylphosphinate, 12g of methyl p-toluenesulfonate, and 1L of toluene, stir evenly, heat to 100°C, react for 2h, and distill under reduced pressure to obtain 668.8g of methyl 3,3-diethoxypropyl methylphosphonate with a GC purity of 94% and a yield of 74.8%.

[0060] Example 5

[0061] (1) Preparation of 3,3-diisopropoxypropylmagnesium chloride (Turbo Grignard reagent)

[0062] Under nitrogen protection, add 133g (5.542mol) of magnesium chips, 32.30g (0.747mol) of lithium chloride and 400mL of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, heat to 55°C, add 1mL of 1,2-dibromoethane under reflux to initiate, then cool to room temperature, slowly add 969.6g (4.979mol) of 1-chloro-3,3-diisopropoxypropane in 2.9L of anhydrous tetrahydrofuran solution, and after the addition is complete, keep warm at 40°C for 2h to obtain a tetrahydrofuran solution of 3,3-dipropoxypropylmagnesium chloride.

[0063] (2) Preparation of dimethyl 3,3-diisopropoxypropylphosphite

[0064] Under nitrogen protection, add 512g (3.985mol) of dimethoxyphosphorus chloride and 1.5L of anhydrous tetrahydrofuran to a 3L four-necked bottle, stir evenly, cool to -15°C, slowly drop the tetrahydrofuran solution of 3,3-diisopropoxypropylmagnesium chloride prepared in the above experiment, keep warm at 30°C for 10h after the dropwise addition. Concentrate under reduced pressure to remove the solvent, recover tetrahydrofuran, slowly drop saturated ammonium chloride solution (540g ammonium chloride / 1.6L water) at 0°C to quench, filter and recover 481g of solid magnesium chloride, add dichloroethane (200mL×3 times) to the filtrate to extract and layer, combine the organic phases, and concentrate under reduced pressure to recover dichloroethane to obtain 884g of dimethyl 3,3-diisopropoxypropylphosphinate.

[0065] (3) Preparation of 3,3-diisopropoxypropylmethylphosphonic acid methyl ester

[0066] Add 884 g of the prepared 3,3-dipropoxypropyl dimethyl phosphite, 18 g of methyl iodide, and 1 L of cyclohexane into a 2 L single-mouth bottle, stir evenly, seal and heat to 80 ° C, react for 4 h, and distill under reduced pressure to obtain 778.5 g of 3,3-diisopropoxypropyl methylphosphonate with GC purity of 95% and a yield of 77%.

Claims

1. A method for preparing 3,3-dialkoxypropylmethylphosphonic acid methyl ester, characterized in that: The 3,3-dialkoxypropylmethylphosphonic acid methyl ester is prepared by reacting dimethoxyphosphonium chloride with a Grignard reagent or a Turbo Grignard reagent, and then undergoing Arbuzov rearrangement under the action of a catalyst. The synthesis route is as follows: ； Wherein, X is selected from Cl, Br, I; R1 is methyl, ethyl or isopropyl; the Grignard reagent is a Grignard reagent obtained by reacting 1-halogenated-3,3-dialkoxypropane with metal magnesium, and the Turbo Grignard reagent is a Turbo Grignard reagent obtained by reacting 1-halogenated-3,3-dialkoxypropane with metal magnesium and auxiliary agent lithium chloride; The following steps are involved: (1) 1-halogenated-3,3-dialkoxypropane reacts with magnesium metal to obtain a Grignard reagent, or lithium chloride is added as an auxiliary agent to obtain a Turbo Grignard reagent, and then reacts with dimethoxyphosphorus chloride to obtain an intermediate product; the reaction temperature of the Grignard reagent or Turbo Grignard reagent and dimethoxyphosphorus chloride is -50°C to 120°C, and the reaction time is 0.5 to 48 hours; (2) Adding or not adding a catalyst to the intermediate product, and subjecting the intermediate product to Arbuzov rearrangement reaction to obtain methyl 3,3-dialkoxypropylmethylphosphonate; the reaction temperature of the intermediate product to Arbuzov rearrangement reaction is 0°C to 220°C, and the reaction time is 0.5 to 48 hours.

2. The method for preparing 3,3-dialkoxypropylmethylphosphonic acid methyl ester according to claim 1, characterized in that: In step (1), when preparing the Grignard reagent, the molar ratio of the 1-halogenated 3,3-dialkoxypropane to metallic magnesium is 1:1-6, and when preparing the Turbo Grignard reagent, the molar ratio of the 1-halogenated 3,3-dialkoxypropane to metallic magnesium and lithium chloride is 1:1-6:0.05-15.

3. The method for preparing 3,3-dialkoxypropylmethylphosphonic acid methyl ester according to claim 1, characterized in that: In step (1), the molar ratio of dimethoxyphosphonium chloride to Grignard reagent or Turbo Grignard reagent is 1:0.5-5.

4. The method for synthesizing 3,3-dialkoxypropylmethylphosphonate according to claim 1, characterized in that: In step (2), one or more of methyl chloride, methyl iodide, dimethyl carbonate, trimethyl phosphate, dimethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, methyl formate and trimethyl orthoformate are added to carry out a catalytic reaction during the Arbuzov rearrangement reaction.

5. The method for synthesizing 3,3-dialkoxypropylmethylphosphonic acid methyl ester according to claim 1, characterized in that: In the preparation process, an organic solvent is used as a reaction solvent, and the organic solvent is tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, n-hexane, cyclohexane, decahydronaphthalene, toluene, xylene, trimethylbenzene, ether, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, N-methylpyrrolidone or dimethyl sulfoxide.

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