Efficient preparation method of diethyl methyl phosphoryl acetate and special device thereof

Abstract

The invention belongs to the technical field of organic phosphorus compound synthesis, and particularly relates to an efficient preparation method of diethyl methyl phosphoryl acetate (the chemical name is diethyl methyl phosphoryl acetate) and a special device thereof. The method comprises the following steps: taking diethyl phosphite and methyl chloroacetate as raw materials, and carrying out C-alkylation reaction in a continuous flow microreactor through gradient temperature control (a preheating zone is 40-60 DEG C, a main reaction zone is 70-85 DEG C, and a quenching zone is 20-30 DEG C) in the presence of a magnetic mesoporous silica loaded Pd-Cu bimetallic catalyst (Pd is 0.5-1.0 wt%, and Cu is 1.0-2.0 wt%). The special device is integrated with a microreactor array (channels are 500 * 300 microns), a ceramic membrane separation unit (molecular weight cutoff is 5-20 kDa) and a falling-film rectifying tower (the number of tower plates is greater than or equal to 30). Through nano-catalysis and process reinforcement synergy, the product yield is greater than or equal to 97.3%, the purity is greater than or equal to 99.2%, the catalyst is recycled for 15 times, and the wastewater CODlt is reduced; and the technical problems of low reaction efficiency, high discharge of three wastes and difficulty in continuation of the traditional process are solved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic phosphorus compound synthesis, and particularly relates to a high-efficiency preparation method and a special device for methylphosphonoacetate diethyl ester (chemical name: methylphosphonoacetate diethyl ester). BACKGROUND

[0002] Methylphosphonoacetate diethyl ester is a key pharmaceutical / pesticide intermediate and is indispensable in the synthesis of antiviral drugs (such as cidofovir) and herbicides (such as glufosinate). Existing industrial synthesis mainly relies on acylation or Grignard reagent method, but there are systematic defects:

[0003] Reaction efficiency bottleneck - traditional acylation process needs to be strictly controlled at low temperature (0-5℃) to inhibit side reactions, but the corrosion of the thionyl chloride catalytic system is strong, leading to increased equipment wear and tear, and low atomic utilization rate (≤70%), with product purity generally <90%, and significant yield fluctuations (65-75%) after industrialization; high environmental cost - the cost of three wastes treatment accounts for more than 30% of the total production cost, and the acid-containing wastewater (230L / ton of product) and magnesium salt-containing solid waste have a heavy ecological load, with COD value of wastewater exceeding 1000mg / L, far exceeding the green process standard; lack of process intrinsic safety - although the Grignard reagent method has a short path, it is highly sensitive to water and oxygen, and the amplification effect causes safety production risks, and the present-use mode restricts continuous production. What is particularly prominent is that existing technologies all need to rely on high-energy separation processes (such as multi-stage extraction, reduced pressure distillation) to purify products, resulting in long process, and a sharp increase in energy consumption. The above defects together make it difficult for traditional processes to meet the core requirements of fine chemical industry for atomic economy, process safety and environmental compatibility, and it is urgent to develop an innovative system with the advantages of high-efficiency catalysis and continuous flow process intensification.

[0004] The existing technologies are summarized in Table 1 below.

[0005] Table 1 Comparison of existing technologies

[0006] Method Reaction temperature Yield Characteristics Waste disposal difficulty Acylation method 0-5℃ 68-72％ Strong corrosive catalyst High (acid-containing wastewater) Grignard reagent method Normal temperature 65-75％ Significant amplification effect Medium (contains magnesium salt solid waste) Phosphite method 80-100℃ 70-80％ Complex by-products High (organic liquid waste) . SUMMARY

[0007] To solve the above prior art problems, the application provides a high-efficiency preparation method of methyl phosphonoacetate diethyl ester and a special device thereof. Taicang Yuntong New Material Technology Co., Ltd. has unique advantages in the field of nanomaterial dispersion technology (see patent CN201810333687.9 for nanosilica dispersion liquid). Based on this background, the application has developed a nanocatalysis coupling continuous flow reaction technology, which realizes the intrinsically safe and green process through the synergistic innovation of mesoporous silica supported catalyst and microchannel reactor. The application solves the problems of harsh reaction conditions, low yield and serious environmental pollution in the traditional process by innovatively introducing a nanocatalysis system and continuous flow microreaction technology, and is suitable for large-scale industrial production.

[0008] The application comprises the following technical solutions:

[0009] A high-efficiency preparation method of methyl phosphonoacetate diethyl ester comprises the following steps:

[0010] Diethyl phosphite and are used as raw materials, and a C-alkylation reaction occurs in a continuous flow microreactor in the presence of a mesoporous silica supported bimetallic catalyst, and the reaction formula is as follows:

[0011]

[0012] (C2H5O)2P(O)H+ClCH2COOCH3+base→(C2H5O)2P(O)CH2COOCH3+salt`.

[0013] The solvent system is an acetonitrile / water mixed solvent.

[0014] The base is preferably triethylamine.

[0015] Further, in the above method, the catalyst is supported on a magnetic mesoporous silica carrier and loaded with Pd-Cu bimetallic active sites, wherein the Pd loading amount is 0.5-1.0 wt%, the Cu loading amount is 1.0-2.0 wt%, the carrier pore size is 4-6 nm, and the specific surface area is >300 m 2 / g. The solvent system is an acetonitrile / water mixed solvent (volume ratio 9:1), which takes into account the nucleophilicity and environmental friendliness.

[0016] This design is derived from the accumulation of nanodispersion technology of Taicang Yuntong in the field, and the metal anchoring ability is enhanced through surface amino modification.

[0017] Further, in the above method, gradient temperature control is adopted during the reaction process, including:

[0018] Preheating zone: 40-60℃

[0019] Main reaction zone: 70-85℃

[0020] Quenching zone: 20-30℃.

[0021] Further, in the above method, the molar ratio of the raw materials is diethyl phosphite: methyl chloroacetate = 1:1.0-1.2, the catalyst is used in an amount of 0.8-1.5 mol%, and the residence time is 60-120 s.

[0022] Further, in the above method, the catalyst is recovered by a membrane separation-magnetic separation coupling technique, the recovery rate is ≥95%, and the number of recycling times is ≥10.

[0023] The application also discloses a special device for implementing the above method, which comprises:

[0024] a microreactor array integrated with a temperature gradient control module;

[0025] an online membrane separation unit using a ceramic membrane with a molecular weight cut-off of 5-20 kDa;

[0026] a falling film rectifying column with a theoretical plate number of ≥30.

[0027] Further, in the above professional device, the microreactor channel has a rectangular cross section, a width of 500±50 μm, a height of 300±30 μm, and is made of corrosion-resistant alloy.

[0028] Further, in the above professional device, a catalyst magnetic separation recovery system is further arranged, and the magnetic field strength is ≥1.0 T.

[0029] Further, in the above professional device, the membrane separation unit is directly communicated with the rectifying column to form a continuous flow product separation system.

[0030] Further, in the above professional device, a molecular sieve dehydration device is arranged on the top of the rectifying column.

[0031] Compared with the prior art, the application has the following outstanding beneficial effects:

[0032] The application breaks through the traditional synthesis bottleneck of methyl phosphonooxyacetate diethyl ester by coupling nano-catalysis and continuous flow process:

[0033] 1. Nano-catalysis technology breakthrough

[0034] - Develop magnetic mesoporous silica nanoparticles (Fe3O4@mSiO2) as a carrier, and graft bimetallic active sites (Pd-Cu) on the surface

[0035] - The catalyst can be recycled ≥15 times (activity attenuation <5%), and the use cost is reduced by 60% compared with traditional homogeneous catalysts

[0036] - Nano confinement effect improves reaction selectivity (byproduct reduction of 40%)

[0037] 2. Process intensification

[0038] - Continuous flow process: multi-stage microchannel reactor (channel size 500 pm) to achieve millisecond mixing

[0039] - Reaction temperature optimization: gradient temperature control (50 °C in the first zone -> 80 °C in the second zone -> 25 °C in the third zone)

[0040] - In-line separation technology: membrane separation-distillation coupling, shortening the process by 2 / 3.

[0041] The specific optimization results are shown in Table 2

[0042] Table 2 Process optimization results

[0043] Parameter Optimization range Optimal value Influence mechanism Reaction temperature 50-85℃ 80℃ > 75 ℃ Accelerate side reactions Catalyst dosage 0.5-3 mol% 1.2 mol% Saturation loading limit of nano-carrier Residence time 30-180s 90s <60s reaction incomplete pH control 8.0-9.5 8.8 > 9.0 Hydrolysis intensifies

[0044] 3. Green chemical properties

[0045] - Atomic utilization rate ≥ 85% (≤ 70% for traditional methods)

[0046] - Reduction of wastewater COD by 90% (< 100 mg / L)

[0047] - Product purity ≥ 99.2% (determined by GC). BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 : Process flow diagram of methyl phosphonoacetate diethyl ester synthesis system, showing: raw material storage tank -> microreactor array -> membrane separator -> rectifying column -> product collection tank, arrow indicating material flow direction, dotted line indicating catalyst circulation path;

[0049] Figure 2 : Cross-sectional view of microreactor internal structure, multi-channel serpentine design (channel cross-sectional size 500 pm x 300 pm), temperature control partition identification (preheating zone / reaction zone / quenching zone);

[0050] Figure 3 : Schematic diagram of nano-catalyst structure, Fe3O4 magnetic core (diameter 50 nm) in the center, mesoporous SiO2 shell (pore size 5 nm) on the outer ring, Pd-Cu bimetallic active site (particle size 2-3 nm) on the outer ring surface;

[0051] Figure 4 : HPLC spectrum of methyl chloroacetate;

[0052] Figure 5 : HPLC spectrum of crude methyl phosphonoacetate diethyl ester;

[0053] Figure 6 : HPLC spectrum of pure methyl phosphonoacetate diethyl ester. DETAILED DESCRIPTION

[0054] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0055] Raw materials and equipment

[0056] Main raw materials:

[0057] Diethyl phosphite (industrial grade, ≥99%)

[0058] Methyl chloroacetate (industrial grade, ≥98%)

[0059] Nano catalyst (self-made SiO2@Pd-Cu)

[0060] Triethylamine (deacidifying agent)

[0061] Equipment configuration (as shown in Figure 1 ):

[0062] Microreaction system (material: hastelloy), as shown in Figure 2 .

[0063] Magnetic separator (magnetic field strength ≥1.2T)

[0064] Falling film rectifying column (vacuum degree ≤-0.095MPa).

[0065] Example 1

[0066] A high-efficiency preparation method of methyl phosphonoacetate diethyl ester, comprising the following steps:

[0067] 1) Catalyst preparation:

[0068] Fe3O4@mSiO2 carrier (magnetic core diameter 50nm, SiO2 shell layer pore size 5nm, as shown in Figure 3 ) is synthesized by sol-gel method

[0069] Impregnate PdCl2 / Cu(NO3)2 mixed solution (Pd:Cu = 1:2 molar ratio), hydrogen reduction (300℃, 4h) to obtain SiO2@Pd-Cu catalyst (Pd 0.6wt%, Cu 1.2wt%);

[0070] 2) Continuous flow reaction:

[0071] Solution A: An acetonitrile solution (concentration 30wt%) consisting of 166g (1.0mol) diethyl phosphite and 106g (1.05mol) triethylamine.

[0072] Solution B: 122.5 g (1.0 mol) of methyl chloroacetate + 1.5 g of catalyst in acetonitrile solution

[0073] Dual-feed pump-in microreactor (channels 500×300μm, Hastelloy material):

[0074] Flow rate: Solution A 10 mL / min, Solution B 12 mL / min (VA:VB = 1:1.2)

[0075] Temperature gradient: Preheating zone 50℃ → Main reaction zone 80℃ → Quenching zone 25℃

[0076] Dwell time: 90 seconds;

[0077] 3) Product separation:

[0078] The catalyst is separated from the reaction solution via a ceramic membrane (with a molecular weight cutoff of 10 kDa);

[0079] The filtrate enters a falling film distillation column (theoretical plate number 35, vacuum degree -0.098MPa):

[0080] The temperature at the top of the tower is 85℃ (for collecting acetonitrile / water).

[0081] The product was collected in the tower at 152℃;

[0082] 4) Catalyst magnetic recovery (magnetic field strength 1.2T), followed by ethanol washing and recycling.

[0083] The results are as follows Figures 4-6 As shown:

[0084] Conversion rate: 99.3% (GC detection)

[0085] Selectivity: 97.8%

[0086] Product purity: 99.2% (GC area normalized)

[0087] Catalyst recovery rate: 98.1%

[0088] Wastewater COD: 85 mg / L.

[0089] Example 2

[0090] The results of the catalyst cycling experiment are shown in Table 3.

[0091] Table 3 Results of catalyst cycling test

[0092] Cycle number Conversion rate Selectivity Product purity 1 99.3％ 97.8％ 99.5％ 5 98.7％ 97.5％ 99.3％ 10 98.1％ 96.9％ 99.0％ 15 97.3％ 96.2％ 98.7％

[0093] Comparative Example

[0094] Traditional acylation method

[0095] Same amount of raw materials, thionyl chloride catalysis (0-5℃ reaction)

[0096] Results: conversion rate 89%, selectivity 82%, purity 90.5%

[0097] Acid-containing wastewater 230L / ton of product was generated.

[0098] Summary:

[0099] The technical solution breaks through the bottleneck of traditional process through the synergistic innovation of nanocatalysis and process intensification, and the product yield is increased to more than 97%, and the three waste emissions are reduced by 90%, fully embodying the concept of green chemistry. The data of the examples show that the catalyst still maintains more than 97% activity after 15 cycles, greatly reduces the production cost, and has significant industrial value.

[0100] It is worth noting that the above examples focus on interpreting the technical solution of the present application, rather than precisely defining its protection scope. Those skilled in the art should understand that based on the technical details disclosed in the examples of the present application, appropriate adjustments and optimizations can be made, or equivalent substitutions can be made to individual or even all technical elements. Such adjustment and substitution measures will not deviate from the core essence of the technical solution of the present application, and should be included in the technical protection scope of the examples of the present application. In short, the protection scope of the present application should not be subject to the concrete presentation of the above examples, but should widely cover all equivalent changes and improvements that do not deviate from its basic concept. In summary, the protection scope of the present application should be based on the statement of the claims, and the above examples are only a reference guide to understand the present application.

Claims

1. A highly efficient method for preparing diethyl methyl phosphoroacetate, characterized in that, Includes the following steps: Using diethyl phosphite and methyl chloroacetate as raw materials, a C-alkylation reaction occurred in a continuous flow microreactor in the presence of a bimetallic catalyst supported on mesoporous silica. The reaction formula is as follows: (C2H5O)2P(O)H + ClCH2COOCH3 + base → (C2H5O)2P(O)CH2COOCH3 + salt; An acetonitrile / water mixed solvent system was used.

2. The method according to claim 1, characterized in that: The catalyst uses magnetic mesoporous silica as a support and loads Pd-Cu bimetallic active sites, wherein the Pd loading is 0.5-1.0 wt%, the Cu loading is 1.0-2.0 wt%, and the support pore size is 4-6 nm.

3. The method according to claim 1, characterized in that: The reaction process employs gradient temperature control, including: Preheating zone: 40-60℃ Main reaction zone: 70-85℃ Quenching zone: 20-30℃.

4. The method according to claim 1, characterized in that: The raw material molar ratio is diethyl phosphite: methyl chloroacetate = 1:1.0-1.2, the catalyst dosage is 0.8-1.5 mol%, and the residence time is 60-120 s.

5. The method according to claim 1, characterized in that: The catalyst is recovered using membrane separation-magnetic separation coupling technology, with a recovery rate of ≥95% and a recycling rate of ≥10 times.

6. A dedicated apparatus for implementing the method according to any one of claims 1-5, characterized in that, include: Microreactor array with integrated temperature gradient control module; The online membrane separation unit uses ceramic membranes with a molecular weight cutoff of 5-20 kDa. Falling film distillation column with ≥30 theoretical plates.

7. The special device according to claim 6, characterized in that: The microreactor channel has a rectangular cross-section, with a width of 500±50μm and a height of 300±30μm, and is made of a corrosion-resistant alloy.

8. The special device according to claim 6, characterized in that: It is also equipped with a catalyst magnetic separation and recovery system with a magnetic field strength ≥1.0T.

9. The special device according to claim 6, characterized in that: The membrane separation unit is directly connected to the distillation column, forming a continuous flow product separation system.

10. The special device according to claim 6, characterized in that: The distillation column is equipped with a molecular sieve dehydration device at the top.

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