A method for the scale-up preparation of dimethylheptyl methylphosphonate

Abstract

The application discloses an amplification preparation method of dimethylheptyl methylphosphonate, and belongs to the technical field of medical intermediates. The core point of the application is that 2-octanol and phosphorus trichloride are used as raw materials, and tri-2-octyl phosphite is generated in an organic solvent in the presence of a catalyst A, then the tri-2-octyl phosphite is reacted with a methylating agent in the presence of a catalyst B to generate dimethylheptyl methylphosphonate. The method avoids the use of dangerous reagents and expensive reagents, reduces the raw material cost, reduces the generation amount of isomers, improves the reaction yield, greatly reduces the amount of three wastes, and makes the whole preparation process more green and environment-friendly. The process is simple and reliable, easy to industrial production, and provides a new reaction path for the synthesis of dimethylheptyl methylphosphonate.

Description

Technical Field

[0001] This invention relates to a scale-up preparation method of dimethylheptyl methylphosphonate, belonging to the field of organophosphorus fine chemicals technology. Background Technology

[0002] Dimethylheptyl methylphosphonate, trade name P350, is a highly efficient neutral organophosphorus extractant. It possesses excellent complexing ability, as well as good chemical stability and radiation resistance. P350 is used for the extraction and separation of rare earth elements, uranium-thorium, cobalt-nickel, scandium, and lithium isotopes.

[0003] Currently, there are two methods for synthesizing dimethylheptyl methylphosphonate:

[0004] 1. Methylphosphonic acid dimethyl ester (DMMP) is reacted with acyl chloride agents such as SOCl2, PCl5 or phosgene under the catalytic conditions of dimethylformamide (DMF), pyridine or tertiary amine to generate methylphosphonic dichloride. Then, methylphosphonic dichloride is reacted with isooctyl alcohol or sodium isooctyl alcohol to obtain the target product P350.

[0005] 2. Using PCl3, anhydrous AlCl3 and 2-octanol as raw materials, a complex CH3PCl4·xAlCl3 was first prepared, and then P350 was obtained by alcoholysis.

[0006] Route 1 has disadvantages such as operational risks and high raw material prices; Route 2 has disadvantages such as slow reaction speed and low yield.

[0007] In summary, the current synthesis of dimethylheptyl methylphosphonate is cumbersome, generates a large amount of waste, has high overall costs, and poses safety hazards. Therefore, developing a simple, reliable, low-cost synthetic route suitable for industrial production is of paramount importance. Summary of the Invention

[0008] To overcome the aforementioned technical deficiencies, this invention provides a scale-up preparation method for dimethylheptyl methylphosphonate. The core of this invention is the use of 2-octanol as a starting material, which reacts with phosphorus trichloride in the presence of a catalyst to generate tri-2-octyl phosphite. The tri-2-octyl phosphite then reacts with a methylating agent to obtain the product. This method significantly shortens the reaction steps, avoids the use of hazardous reagents, reduces raw material costs, and is simple, reliable, and easy to industrialize, providing a new reaction pathway for the synthesis of dimethylheptyl methylphosphonate.

[0009] The scale-up preparation method of dimethylheptyl methylphosphonate described in this invention is represented by the following reaction equation:

[0010]

[0011] Includes the following steps:

[0012] Step 1: Using 2-octanol and phosphorus trichloride as raw materials, tri-2-octyl phosphite is generated in an organic solvent in the presence of alkali and catalyst A;

[0013] Furthermore, in the above technical solution, catalyst A is selected from sodium iodide or potassium iodide.

[0014] Furthermore, in the above technical solution, the alkali is selected from sodium hydride, potassium hydride, pyridine, triethylamine, or N,N-diisopropylethylamine.

[0015] Furthermore, in the above technical solution, the molar ratio of 2-octanol to phosphorus trichloride is 4-5:1; the reaction temperature is 20℃ to 45℃.

[0016] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0017] Step 2: Tri-2-octyl phosphite reacts with a methylating agent in an organic solvent in the presence of catalyst B to generate dimethylheptyl methylphosphonate.

[0018] Furthermore, in the above technical solution, the organic solvent is selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

[0019] Furthermore, in the above technical solution, catalyst B is selected from tetrabutylammonium bisulfate, tetrabutylammonium iodide, tetrabutylammonium fluoride or tetrabutylammonium bromide.

[0020] Furthermore, in the above technical solution, the molar ratio of tri-2-octyl phosphite to the methylating agent is 1:1-2.5; the reaction temperature is 50℃ to 70℃.

[0021] Furthermore, in the above technical solution, the methylating agent is selected from iodomethane, methyl p-toluenesulfonate, methyl methanesulfonate, or dimethyl sulfate.

[0022] Beneficial effects of the invention

[0023] 1) It avoids the use of dangerous reagents such as phosgene and relatively more expensive reagents such as dimethyl methylphosphonate, making it more feasible in actual production and lower in cost.

[0024] 2) It reduces the amount of isomers generated, increases the reaction yield, and greatly reduces the amount of waste, making the entire preparation process greener and more environmentally friendly; the overall production cost is significantly lower than that of existing literature or patents, making the product more competitive in the market. Attached Figure Description

[0025] Figure 1 Example 1 shows the HNMR spectrum of the product dimethylheptyl methylphosphonate. Detailed Implementation

[0026] The present invention will be further illustrated below with reference to specific embodiments. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0027]

[0028] Example 1

[0029] Under controlled temperature of 0-10℃, 2-octanol (3.90 g, 0.03 mol) / pyridine (2.37 g, 0.03 mol) was dissolved in dichloromethane (20 ml), and phosphorus trichloride (1.37 g, 0.01 mol) / dichloromethane solution (3 ml) was added dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. After quenching, the reaction was analyzed by GC, yielding tri-2-octyl phosphite (75.1%), di-2-octyl phosphite (16.4%), and mono-2-octyl phosphite (5.3%). The obtained products were very mixed and could not be used for the next step.

[0030] Example 2

[0031] Under controlled temperature of 0-10℃, 2-octanol (7.81 g, 0.06 mol) / pyridine (4.75 g, 0.06 mol) was dissolved in dichloromethane (40 ml), and phosphorus trichloride (1.37 g, 0.01 mol) / dichloromethane solution (3 ml) was added dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. After quenching, the reaction was analyzed by GC, yielding tri-2-octyl phosphite (76.7%), di-2-octyl phosphite (17.1%), and mono-2-octyl phosphite (4.5%). The obtained products were very mixed and could not be used for the next step.

[0032] Example 3

[0033] At a controlled temperature of 0-10℃, dissolve 2-octanol (3.26g, 0.025mol) / pyridine (2.37g, 0.03mol) in dichloromethane (20ml), and add phosphorus trichloride (1.37g, 0.01mol) / dichloromethane solution (3ml) dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. After quenching, the reaction was detected by GC, yielding tri-2-octyl phosphite (7.6%), di-2-octyl phosphite (90%), and mono-2-octyl phosphite (2.5%). 2-Octanol (1.95 g, 0.015 mol) and sodium iodide (0.15 g, 0.001 mol) were added, and stirring continued for 3 hours. After quenching, the reaction was detected by GC, yielding tri-2-octyl phosphite (83%) and di-2-octyl phosphite (11%). The resulting products were very mixed and could not be used for the next step.

[0034] Example 4

[0035] first step:

[0036] At a controlled temperature of 0-10℃, dissolve 2-octanol (3.26g, 0.025mol) / pyridine (2.37g, 0.03mol) in dichloromethane (20ml), and add phosphorus trichloride (1.37g, 0.01mol) / dichloromethane solution (3ml) dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. 60% sodium hydroxide (0.8 g, 0.02 mol) was added to a 10 ml solution of 2-octanol (1.95 g, 0.015 mol) in dichloromethane. After stirring for 10 minutes, the solution was added to the reaction solution, followed by sodium iodide (0.15 g, 0.001 mol). The mixture was stirred at 20-25℃ for another 3 hours. After quenching, the reaction was detected by GC, yielding tri-2-octyl phosphite (92%). The resulting mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate, and then evaporated to dryness. The tri-2-octyl phosphite was then used directly in the next step.

[0037] Step Two:

[0038] Iodomethane (1.42 g, 0.01 mol) was slowly added to an acetonitrile (10 ml) solution of the product from the first step, tri-2-octyl phosphite, at 70 °C. After reflux and stirring for 2 hours, the reaction was confirmed by HPLC to be complete. The solution was then poured into 1 M hydrochloric acid, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, slurried with petroleum ether, filtered, and dried to obtain 2.28 g of a yellow powder (two-step yield 71%). The yellow powder was characterized as shown in the figure. Figure 1 , 1 H NMR(CDCl3,400M Hz)δ0.85-0.88(t,6H,2CH3),1.26-1.45(m,25H,3CH 3,8CH2),1.48-1.62(m,4H,2CH2),4.47-4.52(m,2H,2CH); ESI-MS m / z:321.03[M+H] + .

[0039] Example 5

[0040] first step:

[0041] At a controlled temperature of 0-10℃, dissolve 2-octanol (3.26g, 0.025mol) / triethylamine (3.04g, 0.03mol) in tetrahydrofuran (20ml), and add phosphorus trichloride (1.37g, 0.01mol) / tetrahydrofuran solution (3ml) dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. 60% sodium hydroxide (0.8 g, 0.02 mol) was added to a tetrahydrofuran (10 ml) solution of 2-octanol (1.95 g, 0.015 mol). After stirring for 10 minutes, it was added to the reaction solution, followed by potassium iodide (0.17 g, 0.001 mol). The mixture was stirred at 20-25℃ for another 3 hours. After quenching, the reaction was detected by GC, yielding tri-2-octyl phosphite (93%). The resulting mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate, and then directly used in the next step after rotary evaporation.

[0042] Step Two:

[0043] Methyl p-toluenesulfonate (1.86 g, 0.01 mol) and tetrabutylammonium hydrogen sulfate (0.34 g, 0.001 mol) were slowly added to an acetonitrile (10 ml) solution of tri-2-octyl phosphite obtained in the previous step at 70 °C. After stirring under reflux for 2 hours, the reaction was detected by HPLC to be complete. The solution was poured into 1 M hydrochloric acid solution, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, pulped with petroleum ether, filtered, and dried to obtain 2.85 g of yellow powder (two-step yield 89%).

[0044] Example 6

[0045] first step:

[0046] Under controlled temperature of 0-10℃, 2-octanol (32.56 g, 0.25 mol) / triethylamine (30.36 g, 0.3 mol) was dissolved in tetrahydrofuran (200 ml), and phosphorus trichloride (13.73 g, 0.1 mol) / tetrahydrofuran solution (30 ml) was added dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. 60% sodium hydroxide (8 g, 0.2 mol) was added to a tetrahydrofuran solution of 2-octanol (19.53 g, 0.15 mol) and stirred for 10 minutes before being added to the reaction solution. Then tetrabutylammonium iodide (3.69 g, 0.01 mol) was added, and the mixture was stirred at 20-25℃ for another 3 hours. After quenching, the reaction was analyzed by GC, yielding tri-2-octyl phosphite (93%). The resulting mixture was used directly in the next step.

[0047] Step Two:

[0048] Dimethyl sulfate (13.87 g, 0.11 mol) and tetrabutylammonium iodide (3.69 g, 0.01 mol) were slowly added to an acetonitrile (10 ml) solution of tri-2-octyl phosphite obtained in the previous step at 70 °C. After stirring under reflux for 2 hours, the reaction was detected by HPLC to be complete. The solution was poured into 1 M hydrochloric acid solution, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, pulped with petroleum ether, filtered, and dried to obtain 26.92 g of yellow powder (two-step yield 84%).

[0049] Example 7

[0050] first step:

[0051] Under controlled temperature of 0-10℃, 2-octanol (3.25 kg, 25 mol) / triethylamine (3.04 kg, 30 mol) was dissolved in tetrahydrofuran (20 L), and phosphorus trichloride (1.37 kg, 10 mol) / tetrahydrofuran solution (3 L) was added dropwise over 10 minutes. The reaction solution was stirred at 20-25℃ for 5 hours. 60% sodium hydroxide (0.8 kg, 20 mol) was added to a tetrahydrofuran solution of 2-octanol (1.95 kg, 15 mol) and stirred for 10 minutes before being added to the reaction solution. Potassium iodide (0.17 kg, 1 mol) was then added, and the mixture was stirred at 20-25℃ for another 3 hours. After quenching, the reaction was analyzed by GC, yielding tri-2-octyl phosphite (92%). The resulting mixture was quenched with water, extracted with dichloromethane, dried over sodium sulfate, and then evaporated to dryness for use in the next step.

[0052] Step Two:

[0053] Iodomethane (2.84 kg, 20 mol) and tetrabutylammonium iodide (0.37 kg, 1 mol) were slowly added to an acetonitrile (20 L) solution of tri-2-octyl phosphite obtained in the previous step at 70 °C. After stirring under reflux for 2 hours, the reaction was detected by HPLC to be complete. The solution was poured into 1 M hydrochloric acid solution, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, pulped with petroleum ether, filtered, and dried to obtain 2.60 kg of yellow powder (yield 81%).

[0054] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for the large-scale preparation of dimethylheptyl methylphosphonate, characterized in that, Includes the following steps: ; Step 1: Using 2-octanol and phosphorus trichloride as raw materials, tri-2-octyl phosphite is generated in an organic solvent in the presence of a base and catalyst A; the catalyst A is selected from sodium iodide or potassium iodide; the base is selected from sodium hydride and pyridine or sodium hydride and triethylamine. Step 2: Tri-2-octyl phosphite reacts with a methylating agent in an organic solvent in the presence of catalyst B to generate dimethylheptyl methylphosphonate; the catalyst B is selected from tetrabutylammonium bisulfate, tetrabutylammonium iodide, tetrabutylammonium fluoride or tetrabutylammonium bromide.

2. The scale-up preparation method of dimethylheptyl methylphosphonate according to claim 1, characterized in that: In the first step, the molar ratio of 2-octanol to phosphorus trichloride is 4-5:1; the reaction temperature is 20℃ to 45℃.

3. The scale-up preparation method of dimethylheptyl methylphosphonate according to claim 1, characterized in that: In the first step, the organic solvent is selected from dichloromethane, tetrahydrofuran, or 2-methyltetrahydrofuran.

4. The scale-up preparation method of dimethylheptyl methylphosphonate according to claim 1, characterized in that: In the second step, the organic solvent is selected from acetonitrile, tetrahydrofuran, or 2-methyltetrahydrofuran.

5. The method for large-scale preparation of dimethylheptyl methylphosphonate according to claim 1, characterized in that: In the second step, the molar ratio of tri-2-octyl phosphite to the methylating agent is 1:1-2.5; the reaction temperature is 50℃ to 70℃.

6. The scale-up preparation method of dimethylheptyl methylphosphonate according to claim 1, characterized in that: The methylating agent is selected from iodomethane, methyl p-toluenesulfonate, methyl methanesulfonate, or dimethyl sulfate.

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