A method for efficiently synthesizing triethyl phosphoacetate

Abstract

The present invention provides a method for efficiently synthesizing triethyl phosphoacetate, which uses diethyl phosphite and ethyl chloroacetate as reaction raw materials, adds a base (including but not limited to sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium tert-amyloxide and other strong bases), and according to the SN2 reaction characteristics, the P-H bond can be smoothly converted into P in the reaction system. ‑ , thereby further attacking the C-Cl bond of ethyl chloroacetate. The solvation effect of polar aprotic solvents can promote the SN2 reaction. Selecting beneficial solvents (including but not limited to toluene, acetonitrile, dichloromethane, tetrahydrofuran, acetone, ether, ethanol, cyclohexane, etc.) can effectively shorten the reaction time and increase the selectivity of triethyl phosphoacetate. Triethyl phosphoacetate can be obtained in a 92% yield and 99.8% purity after a 0.5-hour reaction at room temperature. This method offers the advantages of low energy consumption, high efficiency, and simple operation steps.

Description

Technical Field

[0001] The present invention relates to an SN2 reaction in the field of organic synthesis, and in particular to a method for efficiently synthesizing triethyl phosphoacetate. Background Art

[0002] The organophosphorus compound triethyl phosphoacetate is an important chemical with numerous excellent properties. Triethyl phosphoacetate is a key Wittig-Horner reagent used in intramolecular Heck-type cyclization and isomerization reactions in the Horner-Wadsworth-Emmons reaction. It is also a crucial intermediate in the manufacture of natural compounds such as vitamins, pharmaceuticals, and insect pheromones.

[0003] Triethyl phosphoacetate is not only a widely used organophosphorus synthesis reagent, but also an important raw material for the synthesis of drugs and phenylacrylates (such as 3-phenyl-ethyl phenylacrylate), an intermediate of polymer materials with high strength and excellent waterproof properties.

[0004] Currently, the Arbuzov reaction, which constructs phosphorus-carbon bonds, is an effective route for preparing compounds such as hydrocarbyl phosphonates, phosphinates, and phosphine oxides. First discovered by Michaelis in 1898 and later developed by Arbuzov, the Arbuzov reaction primarily involves the reaction of alkyl phosphonates with halogenated hydrocarbons and phosphates as substrates. The difficulty of the Arbuzov reaction for halogenated hydrocarbons depends on two factors: first, the polarity of the carbon-halogen bond; the stronger the polarity, the easier it is to react, e.g., RI>RBr>RCl; and second, the steric hindrance of the hydrocarbon group; the greater the hindrance, the more difficult it is to react. Generally, aromatic halides are less susceptible to the Arbuzov reaction. The low activity of some chlorinated hydrocarbons, the limited reaction temperature, and the long reaction time greatly limit the application of this reaction in organic synthesis.

[0005] Using triethyl phosphite and ethyl chloroacetate as raw materials, triethyl phosphite can be synthesized via the Arbuzov reaction. However, this method requires relatively high temperatures (120-150°C), and the product is prone to deterioration and yellowing at high temperatures, reducing product quality. Ethyl chloride, another product of the reaction, is also hazardous at these temperatures. Furthermore, triethyl phosphite is sensitive to air and humidity and easily deteriorates during storage, requiring specialized conditions for transportation and storage. When used as a raw material in the synthesis of triethyl phosphite, the product is prone to yellowing.

[0006] Diethyl phosphite, a byproduct of the synthesis of triethyl phosphite, is more chemically stable than triethyl phosphite, has no pungent odor, and is easy to store and transport. Therefore, we use diethyl phosphite as the reaction raw material. Using beneficial solvents (including but not limited to toluene, acetonitrile, dichloromethane, tetrahydrofuran, acetone, ether, ethanol, and cyclohexane), adding a base (including but not limited to sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, sodium ethoxide, triethylamine, liquid ammonia, and aqueous ammonia), and adding ethyl chloroacetate dropwise at room temperature, the reaction is complete. This method is highly efficient, mild, and easy to operate. Furthermore, the synthesized triethyl phosphoacetate product did not turn yellow or deteriorate after one month of storage without inert gas protection. Summary of the Invention

[0007] This invention primarily demonstrates a highly efficient method for synthesizing triethyl phosphoacetate. Using diethyl phosphite and ethyl chloroacetate as the reaction raw materials, and leveraging the characteristics of the SN2 reaction with a beneficial solvent and base catalysis, the method significantly improves reaction efficiency and allows for rapid completion of the reaction at room temperature. Compared to synthesizing triethyl phosphoacetate via the Arbuzov reaction using triethyl phosphite as the reaction raw material, this invention utilizes readily available and stable raw materials, operates under mild and controllable reaction conditions, and produces a more stable triethyl phosphoacetate product.

[0008] The technical solutions of the present invention are as follows:

[0009] .

[0010] The reaction equation is as above. Weigh diethyl phosphite into a reaction flask, add a solvent and a base, mix well, add ethyl chloroacetate dropwise, and after the reaction is complete, extract and distill to obtain a colorless and transparent product, triethyl phosphoacetate.

[0011] The reaction solvent includes but is not limited to toluene, acetonitrile, dichloromethane, tetrahydrofuran, acetone, ether, ethanol, and cyclohexane.

[0012] Polar aprotic solvents are preferably used, as the solvation effect can promote the (SN2) reaction.

[0013] When a polar aprotic solvent is used, the reaction can be completed by adding ethyl chloroacetate dropwise at room temperature.

[0014] The base is sodium alkoxide, which includes sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, and sodium tert-amyl alcohol.

[0015] The molar ratio of diethyl phosphite, ethyl chloroacetate and sodium alcoholate is 1-4:1-4:1-10.

[0016] Preferably, the extraction is performed using ethyl acetate and saturated aqueous NaCl solution to obtain an organic phase.

[0017] Furthermore, the distillation extraction temperature is 146 ℃ ~ 160 ℃, and the pressure is 1 kpa ~ 4 kpa.

[0018] The beneficial effects of the present invention are as follows:

[0019] The present invention abandons the traditional method of synthesizing triethyl phosphoacetate products by Arbuzov reaction, uses diethyl phosphite as a reaction raw material, and efficiently synthesizes triethyl phosphoacetate by SN2 reaction and ethyl chloroacetate in the presence of a beneficial solvent and base catalysis. It is worth noting that the reaction can occur at room temperature, and the reaction rate is extremely high. The reaction conditions are mild and controllable, avoiding high temperature, high pressure and high-risk gas generation. The product yield obtained by the technical solution of the present invention can reach 60% or more, more preferably more than 80%, more preferably more than 90%, and more preferably more than 95%. The product is placed in an open environment at room temperature for 1 month without causing the problem of yellowing of the product and decreased purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the temperament test result diagram of Example 4.

[0021] Figure 2 This is the gas phase result diagram of the reaction mother liquor in Example 5.

[0022] Figure 3 This is the gas phase diagram of the product obtained after distillation in Example 5.

[0023] Figure 4 This is the hydrogen spectrum of the product obtained after distillation in Example 5.

[0024] Figure 5 This is the carbon spectrum of the product obtained after distillation in Example 5. Specific implementation plan

[0025] In order to better understand the characteristics and advantages of the present invention, further description will be given based on the following examples to show various scenarios in the reaction design, but the content of the present invention is not limited to the following examples.

[0026] Example 1

[0027] Diethyl phosphite (13.81 g) and sodium carbonate (5.3 g) were dispersed in acetonitrile (39.5 g) in a three-necked flask. The mixture was then heated to 50°C and allowed to react for 30 minutes, at which point the pH of the reaction system reached 12-14. Ethyl chloroacetate (12.255 g) was then added dropwise. After completion, the internal temperature was raised to 70°C and the reaction was continued, with gas chromatography monitoring the reaction. Gas chromatography revealed that after 8 hours of reaction at 70°C, very little product was produced, with a yield of only 0.11% in the reaction mother liquor. A significant amount of raw material remained unreacted. At the end of the reaction, the pH of the system was 10-12, indicating that the sodium carbonate was too weak to react effectively with diethyl phosphite.

[0028] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium carbonate = 1:1:0.5.

[0029] Example 2

[0030] Diethyl phosphite (13.81 g) and sodium hydroxide (5.3 g) were dispersed in acetonitrile (39.5 g) in a three-necked flask. The mixture was then heated to 50°C and incubated for 30 minutes, at which point the pH of the reaction system reached ≥14. Ethyl chloroacetate (12.255 g) was then added dropwise. After completion, the internal temperature was raised to 70°C and incubated for 13 hours, with gas chromatography monitoring the reaction. Gas chromatography monitored the reaction at 70°C for 13 hours, revealing that a certain amount of product was initially generated, followed by a very slow increase in product content. After 13 hours of incubation, the product yield in the reaction mother liquor was only 9.53%, indicating that a large amount of raw material had not reacted completely. At the end of the reaction, the pH was 12-14, indicating that the sodium hydroxide was not sufficiently alkaline to react effectively with diethyl phosphite.

[0031] Note: The reaction feed molar ratio is diethyl phosphite: ethyl chloroacetate: sodium hydroxide = 1:1:1.

[0032] Example 3

[0033] Diethyl phosphite (13.81 g) and sodium ethoxide (6.8 g) were dispersed in toluene (43.6 g) in a three-necked flask. The mixture was then heated to 70°C and allowed to react for 30 minutes, at which point the pH of the reaction system reached >14. Ethyl chloroacetate (12.255 g) was then added dropwise. After completion, the internal temperature was raised to 95°C and the reaction was continued, monitored by gas chromatography. After 3 hours of heating, gas chromatography revealed that the diethyl phosphite (1.99%) had essentially reacted, with a small amount of ethyl chloroacetate (10.61%) remaining unreacted. The final yield of triethyl phosphoacetate was 64.41%. The pH of the solution was 6-7 after the reaction. This method generates a significant amount of impurities.

[0034] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium ethoxide = 1:1:1.

[0035] Example 4

[0036] Diethyl phosphite (15.19 g) and sodium ethoxide (8.16 g) were dispersed in toluene (43.6 g). After uniform dispersion in a three-necked flask, the internal temperature was raised to 50 ° C and kept warm for 30 minutes. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise. After completion, the internal temperature was raised to 70 ° C and kept warm for reaction. The reaction was monitored by gas chromatography. After 5.5 hours of keeping warm at 70 ° C, the raw materials were basically reacted, and the yield of triethyl phosphoacetate was 74.32%. There was an unknown impurity peak with a content of 10.26% at a retention time of 11.309 min in the gas phase data. The possible chemical structure was inferred by gas chromatography-mass spectrometry as shown in the attached figure. Figure 1 As shown, after the reaction is completed, the pH of the solution is 6-7. Compared with Example 3, the amount of diethyl phosphite used in this example is increased, and the triethyl phosphoacetate product consumes sodium ethoxide to generate additional Figure 1 The impurities described above make the pH value remain at 6-7 after the reaction at this feed ratio.

[0037] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium ethoxide = 1.1:1:1.2.

[0038] Example 5

[0039] Diethyl phosphite (15.19 g) and sodium ethoxide (8.16 g) were dispersed in acetonitrile (39.5 g) and stirred at room temperature in a three-necked flask. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise at room temperature. The two steps took a total of 30 minutes. After the addition was completed, the gas chromatography test results showed that the gas phase content of ethyl chloroacetate was 3.73%, the gas phase content of diethyl phosphite was 0.66%, and the gas phase content of the product triethyl phosphoacetate in the reaction mother liquor was 80.24%. The product was a colorless transparent liquid. After the reaction was completed, the pH of the system was 6-7.

[0040] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium ethoxide = 1.1:1:1.2.

[0041] The reaction mixture was filtered and, after removing the sodium chloride salt, distilled. The distillation apparatus consisted of a distillation column, a distillation head, a reflux ratio controller, and a vacuum receiver. The distillation column was preferably an electrically heated column 1 meter long. The system pressure was controlled at 1 kPa, the liquid temperature in the distillation kettle was 160°C, the temperature of the lower section of the electrically heated column was 150°C, the temperature of the upper section was 146°C, and the steam temperature was 146°C. The purity of the product after distillation reached 99.8%. The colorless, transparent liquid triethyl phosphoacetate after distillation was weighed and found to weigh 20.63 g, for a final yield of 92%.

[0042] When the triethyl phosphoacetate synthesized and distilled from diethyl phosphite was stored in an open environment without any protective gas for one month, its properties remained unchanged and the product remained a colorless, transparent liquid with a purity of 99.8%. However, the triethyl phosphoacetate synthesized from triethyl phosphite at high temperatures (120°C-140°C) turned yellow after one month, becoming a pale yellow, transparent liquid. Its purity decreased by 5-10% (from 99.0% to approximately 90%). Triethyl phosphite may be the root cause of the deterioration.

[0043] Example 6

[0044] Diethyl phosphite (15.19 g) and sodium methoxide (6.48 g) were dispersed in acetonitrile (39.5 g) and stirred at room temperature in a three-necked flask. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise at room temperature. The two steps took a total of 30 minutes. After the addition was completed, purification was carried out according to the method of Example 5. The final product, triethyl phosphoacetate, had a yield of 91.1% and a purity of 99.7%. The product was a colorless, transparent liquid. After the reaction was completed, the pH of the system was 6-7.

[0045] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium methoxide = 1.1:1:1.2.

[0046] Example 7

[0047] Diethyl phosphite (15.19 g) and sodium propoxide (9.85 g) were dispersed in acetonitrile (39.5 g) and stirred at room temperature in a three-necked flask. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise at room temperature. The two steps took a total of 30 minutes. After the addition was completed, purification was carried out according to the method of Example 5. The final product, triethyl phosphoacetate, had a yield of 91.8% and a purity of 99.8%. The product was a colorless, transparent liquid. After the reaction was completed, the pH of the system was 6-7.

[0048] Note: The molar ratio of the reaction materials is diethyl phosphate: ethyl chloroacetate: sodium propoxide = 1.1:1:1.2.

[0049] Example 8

[0050] Diethyl phosphite (15.19 g) and sodium butoxide (11.53 g) were dispersed in acetonitrile (39.5 g) and stirred at room temperature in a three-necked flask. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise at room temperature. The two steps took a total of 30 minutes. After the addition was completed, purification was carried out according to the method of Example 5. The final product, triethyl phosphoacetate, had a yield of 91.6% and a purity of 99.6%. The product was a colorless, transparent liquid. After the reaction was completed, the pH of the system was 6-7.

[0051] Note: The molar ratio of the reaction materials is diethyl phosphate: ethyl chloroacetate: sodium butoxide = 1.1:1:1.2.

[0052] Example 9

[0053] Diethyl phosphite (15.19 g) and sodium tert-amyl alcohol (13.22 g) were dispersed in acetonitrile (39.5 g) and stirred at room temperature in a three-necked flask. At this time, the pH of the reaction system was greater than 14. Then, ethyl chloroacetate (12.255 g) was added dropwise at room temperature. The two steps took a total of 30 minutes. After the addition was completed, purification was carried out according to the method of Example 5. The final product, triethyl phosphoacetate, had a yield of 91% and a purity of 99.7%. The product was a colorless, transparent liquid. After the reaction was completed, the pH of the system was 6-7.

[0054] Note: The molar ratio of the reaction materials is diethyl phosphite: ethyl chloroacetate: sodium tert-amyl alcohol = 1.1:1:1.2.

[0055] Example 10

[0056] The triethyl phosphoacetate products of Examples 6 to 9 were all left open in an environment without any gas protection for one month. The purity, color, and properties of the products did not change. This confirms that the triethyl phosphoacetate products synthesized using diethyl phosphite and ethyl chloroacetate as raw materials and sodium alkoxide as a base have very good stability.

[0057] In summary, a method for efficiently synthesizing triethyl phosphoacetate using diethyl phosphite and ethyl chloroacetate as the reaction raw materials can be rapidly reacted at room temperature under alkaline conditions to obtain triethyl phosphoacetate with a yield of 92% and a purity of 99.8%. This method has the advantages of readily available raw materials, high reaction efficiency, mild and controllable reaction conditions, and a more stable product that is less susceptible to deterioration.

[0058] The above examples are merely preferred embodiments of the present invention. The scope of protection of the present invention is not limited to these examples. All implementation methods derived from the principles of the present invention are also within the scope of protection of the present invention. It should be noted that for researchers in this field, improvements and modifications based on the reaction principles and concepts described in this invention should also be considered within the scope of protection of the present invention.

Claims

1. A method for efficiently synthesizing triethyl phosphoacetate, characterized in that: The following steps are involved: Add solvent and base to diethyl phosphite and mix them evenly. Then slowly add ethyl chloroacetate dropwise. After the reaction is complete, extract and distill to obtain colorless and transparent triethyl phosphoacetate product. The reaction formula is as follows: ； The base is sodium alkoxide, and the sodium alkoxide is selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, and sodium tert-amyloxide; The reaction solvent is selected from toluene and acetonitrile; the molar ratio of diethyl phosphite, ethyl chloroacetate and sodium alkoxide is 1-4:1-4:1-10; After adding the base, the reaction is carried out at a temperature of 10°C~30°C for 0.1h~0.5h; after adding ethyl chloroacetate dropwise, the reaction is carried out at a temperature of 10°C~30°C for 0.1h~0.5h.

2. The method according to claim 1, characterized in that The organic phase was extracted with ethyl acetate and saturated aqueous NaCl solution.

3. The method according to claim 1, characterized in that The extraction temperature of distillation is 146 ℃~160 ℃, and the pressure is 1 kpa~4 kpa.

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