A method for synthesizing tetra[(neopentanoyloxy)methyl] methylene diphosphonate

Abstract

The present disclosure relates to a synthesis method of tetra[(pivaloyloxy)methyl]methylenediphosphonate, which comprises: dissolving or suspending a substrate in an organic solvent, adding at least a reaction catalyst for reaction, the substrate being SM1 and SM2, the organic solvent being acetonitrile and / or toluene, and the reaction catalyst being an iodine-containing catalyst; after the reaction is completed, the reaction solution is treated to obtain a target compound, the target compound being tetra[(pivaloyloxy)methyl]methylenediphosphonate, and the treatment including: adding water and MTBE to the reaction solution for extraction and separation to obtain an organic phase; washing the organic phase with sodium sulfite solution and water in sequence, then performing vacuum desolventization on the organic phase, and using n-heptane for replacement and evaporation treatment to obtain a target compound crude product; adding n-heptane to the target compound crude product, and performing beating, filtration and drying treatment on the target compound crude product. The present disclosure uses an iodine-containing catalyst to replace a traditional strong acid catalyst to efficiently catalyze the synthesis of tetra[(pivaloyloxy)methyl]methylenediphosphonate under mild conditions, the catalyst can be removed only by water washing, and the post-treatment only needs one beating purification, thereby realizing the green and simple preparation of a high-yield and high-purity product.

Description

Technical Field

[0001] This disclosure relates to the field of organic synthesis technology, and in particular to a method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate. Background Technology

[0002] Tetra[(neovaleroxy)methyl]methylene bisphosphonate (POM ester) is a class of symmetrical organophosphorus compounds containing four neopentyloxy active groups and a methylene-bridged bisphosphonate skeleton. It possesses lipophilicity, chemical stability, and structural modifiability, making it suitable for use as a pharmaceutical intermediate, flame retardant, and polymer modifier in the biopharmaceutical and fine chemical industries. Early bisphosphonate products were mainly alkyl or hydroxymethyl substituted derivatives, generally exhibiting high water solubility, poor lipophilicity, and insufficient thermal stability, limiting their application in high-end sectors. POM esters addressed these issues by introducing a sterically hindered neopentyloxy hydrophobic group; however, due to their complex molecular structure and the susceptibility to side reactions from multiple functional groups, their synthesis was difficult, initially limited to small-scale laboratory synthesis and unable to achieve industrial-scale production.

[0003] Current POM ester synthesis technology suffers from the following drawbacks: poor reaction selectivity, traditional one-step esterification condensation easily produces mono- and tri-substituted byproducts, and product purity is generally below 90%; harsh reaction conditions, typically requiring high-temperature reflux above 110°C and high-vacuum dehydration, with reaction times exceeding 12 hours, resulting in poor batch stability; the use of strong acid catalysts such as concentrated sulfuric acid and p-toluenesulfonic acid, which are highly corrosive and easily lead to substrate carbonization and product oxidation and discoloration, and post-treatment requires large amounts of alkali solution for neutralization, generating high-salt wastewater; and yields are only 65%~75%, requiring multiple recrystallizations or vacuum distillation for purification, resulting in high costs and hindering industrialization. Summary of the Invention

[0004] To address the technical problems in the current synthesis schemes of tetra[(neopentyloxy)methyl]methylene diphosphonate, such as harsh reaction conditions, equipment corrosion and large amounts of waste caused by the use of strong acid catalysts, low yields, and cumbersome post-processing purification, this disclosure proposes a method for synthesizing tetra[(neopentyloxy)methyl]methylene diphosphonate. This method can efficiently synthesize the target product under mild conditions, avoids the use of strong acid catalysts, and allows for easy removal of the catalyst by water washing. Post-processing only requires a single slurrying step to obtain a high-yield and high-purity product.

[0005] This disclosure provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate, the method comprising: The substrate is dissolved or suspended in an organic solvent, and at least a reaction catalyst is added to carry out the reaction. The substrate is SM1 and SM2, the organic solvent is acetonitrile and / or toluene, and the reaction catalyst is an iodine-containing catalyst, which includes inorganic iodides, quaternary ammonium iodides, iodine-containing phosphorus iodides, and imidazole iodides. SM1 is a compound as shown in formula (I), and SM2 is a compound as shown in formula (II).

[0006]

[0007] After the reaction is complete, the reaction solution is post-treated to obtain the target compound, which is tetrakis[(neovaleroxy)methyl]methylene diphosphonate. The post-treatment includes the following steps: Water and MTBE were added to the reaction solution for extraction and separation to obtain the organic phase; The organic phase was washed sequentially with sodium sulfite solution and water, then subjected to desolvation under reduced pressure, and then distilled with n-heptane to obtain the crude target compound. n-Heptane was added to the crude target compound, and the crude target compound was then pulped, filtered, and dried.

[0008] In a further embodiment, the reaction catalyst is a quaternary ammonium iodide, which includes tetrabutylammonium iodide, tetraethylammonium iodide, tetramethylammonium iodide, benzyltriethylammonium iodide, trioctylmethylammonium iodide, hexadecyltrimethylammonium iodide, tetrahexylammonium iodide, and 1-methyl-1,4-diazabicyclo[2.2.2]octane-1-ammonium iodide.

[0009] In a further embodiment, the reaction catalyst is tetraethylammonium iodide, and the equivalent of the tetraethylammonium iodide is 0.2 eq.

[0010] In a further embodiment, the addition of at least a reaction catalyst to carry out the reaction includes: Add the reaction catalyst and heat the reaction solution until the temperature of the reaction solution reaches the preset reaction temperature. The reaction solution is kept at the preset reaction temperature until the preset reaction time is reached.

[0011] In a further embodiment, the preset reaction temperature is 80℃~110℃; the preset reaction time is 6h~24h.

[0012] In a further embodiment, the pulping, filtration, and drying of the crude target compound includes: At 20℃~25℃, the crude product of the target compound is stirred and pulped until the stirring and pulping time reaches the first preset stirring time. The crude target compound is cooled until its temperature drops to 2°C to 8°C, and the crude target compound is stirred and pulped until the stirring and pulping time reaches the second preset stirring time. The crude product of the target compound was filtered, and the resulting filter cake was air-dried.

[0013] In a further embodiment, the addition of at least a reaction catalyst for the reaction further includes the addition of a phase transfer catalyst, wherein the phase transfer catalyst is any one of 12-crown-4, 15-crown-5, or 18-crown-6.

[0014] In a further embodiment, the inorganic iodide includes sodium iodide, potassium iodide, lithium iodide, calcium iodide, magnesium iodide, aluminum iodide, cuprous iodide, and zinc iodide. The iodine-containing phosphonium salt iodides include tetrabutylphosphonium iodide, triphenylmethylphosphonium iodide, tetraphenylphosphonium iodide, and tributyltetradecylphosphonium iodide; The imidazole iodides include tetramethyl iodoureate, 1-ethyl-3-methylimidazolium iodide, and 1-hexyl-3-methylimidazolium iodide.

[0015] In a further embodiment, the equivalent of the reaction catalyst is 0.1 eq to 5 eq, and the equivalent of SM2 is 4 eq to 8 eq.

[0016] In a further embodiment, the volume of the organic solvent is 4V to 10V.

[0017] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit this disclosure.

[0018] Implementing this disclosure will have the following beneficial effects: This disclosure utilizes an iodine-containing catalyst to replace the traditional strong acid catalyst, enabling efficient catalysis of the SM1 and SM2 reactions under mild conditions without the need for additional strong acid. The reaction system exhibits no strong corrosive effect on the reaction equipment, eliminating the need for special anti-corrosion treatment and reducing the investment cost of production equipment. Simultaneously, it avoids the large amounts of high-salt waste acid and wastewater generated by traditional processes, significantly reducing the discharge of waste gas, wastewater, and solid waste, thus better meeting the requirements of green production. Furthermore, the catalyst can be removed simply by water washing, eliminating the need for additional catalyst removal steps. Post-treatment only requires a single n-heptane slurry to obtain a high-purity product. Compared to traditional purification methods involving multiple recrystallizations or column chromatography, the process is significantly simplified, the operation is easier, and product loss during purification is reduced, further improving the final yield. It also reduces solvent consumption and production costs during purification, demonstrating promising prospects for industrial application. Detailed Implementation

[0019] The technical solutions in the embodiments of this specification will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this specification, and not all embodiments. Based on the embodiments in this specification, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0020] It should be noted that the terms "first," "second," etc., used in the specification and claims of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those described herein.

[0021] The term “exemplary” as used herein means “serving as an example, embodiment, or illustration.” Any embodiment illustrated herein as “exemplary” is not necessarily to be construed as superior to or better than other embodiments.

[0022] Prior to the development of this invention, the synthesis techniques for POM esters and similar methylene diphosphonate derivatives generally suffered from low yields. Currently reported synthesis methods mainly include the following five, and the process characteristics and limitations of each method are shown in Table 1.

[0023] Table 1. Current POM ester synthesis routes and their impact on analysis.

[0024] Related literature: Route 1: Vepsäläinen, M., et al. Bisphosphonate prodrugs: A newsynthetic strategy to tetraacyloxymethyl esters of methylenebisphosphonates[J]. Tetrahedron Letters, 1999, 40(34): 6179-6182.DOI: 10.1016 / S0040-4039(99)01223-7 Route 2: Tanaka, S., et al. Targeting Cancer Cells with a BisphosphonateProdrug[J]. Journal of Medicinal Chemistry, 2017, 60(19): 7902–7913.PMID:28891343; PMC: PMC5605902 Route 3: Merkus, D., et al. Scalable Synthesis of Tetrakis-POMMethylenebisphosphonate for Bisphosphonate Prodrug Manufacturing[J].Pharmacological Research, 2019, 141: 32–45. DOI: 10.1016 / j.phrs.2018.12.009 Route 4: Hwang, Y., Cole, P. Efficient in-situ generation of iodomethylpivalate for phosphonate prodrug synthesis[J]. Organic Letters, 2004, 6(18):3001–3004. DOI: 10.1021 / ol049340k Route 5: McKenna, CE, Schmidhauser, J. Functional selectivity inphosphonate ester dealkylation with bromotrimethylsilane[J]. Journal of the American Chemical Society, 1979, 101(21): 6481–6484. DOI: 10.1021 / ja00517a06481 As shown in Table 1, the existing technology has the following drawbacks: First, the reaction selectivity is poor and there are many byproducts. Traditional processes often use a one-step esterification condensation reaction, in which methylene bisphosphonic acid reacts directly with neopentyloxymethanol. The bisphosphonic acid groups in the molecule have uneven activity, and mono- and tri-substituted byproducts are easily produced. The purity of the product is generally less than 90%, which cannot meet the standards for pharmaceutical applications.

[0025] Second, the reaction conditions are harsh and energy consumption is high. Early laboratory processes required high-temperature reflux (above 110°C) and high-vacuum dehydration, with reaction times exceeding 12 hours. This resulted in high energy consumption and demanding equipment requirements. While small-scale laboratory synthesis was feasible, industrial-scale mass production was highly susceptible to batch instability issues.

[0026] Third, the catalyst system has obvious defects. Traditional processes often use strong acid catalysts such as concentrated sulfuric acid and p-toluenesulfonic acid, which have strong catalytic activity but are extremely corrosive, easily causing substrate carbonization and product oxidation and discoloration. Moreover, catalyst residues are difficult to remove, and post-treatment requires a large amount of alkaline solution for neutralization and water washing, generating a large amount of saline wastewater, which puts great pressure on environmental protection and has low atom economy.

[0027] Fourth, the yield is low and the cost is high. The traditional process yields only 65%-75% of the target product, resulting in low raw material utilization. In addition, the purification process is complex (multiple recrystallizations and vacuum distillation), which significantly increases production costs and leads to high prices, thus restricting the industrialization development of downstream industries.

[0028] Example 1

[0029] To address the aforementioned technical problems, this disclosure provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate (POM ester), the synthesis steps of which are as follows:

[0030] Specifically, the methods include: S101. Dissolve or suspend the substrate in an organic solvent, and add at least a reaction catalyst to carry out the reaction. The substrate is SM1 and SM2, the organic solvent is acetonitrile and / or toluene, and the reaction catalyst is an iodine-containing catalyst, which includes inorganic iodides, quaternary ammonium iodides, iodine-containing phosphorus iodides, and imidazole iodides. SM1 is a compound as shown in formula (I), and SM2 is a compound as shown in formula (II). The inorganic iodides include sodium iodide, potassium iodide, lithium iodide, calcium iodide, magnesium iodide, aluminum iodide, cuprous iodide, and zinc iodide. The equivalent amount of the reaction catalyst is 0.1 eq to 5 eq, and the equivalent amount of SM2 is 4 eq to 8 eq. The volume of the organic solvent is 4 V to 10 V.

[0031] ; ; Wherein, the addition of at least a reaction catalyst for the reaction includes: The reaction catalyst is added, and the reaction solution is heated until the temperature of the reaction solution reaches the preset reaction temperature; the preset reaction temperature is 80℃~110℃. The reaction solution is kept at the preset reaction temperature until the preset reaction time is reached; the preset reaction time is 6h to 24h.

[0032] For example, in this embodiment, acetonitrile is selected as the organic solvent and sodium iodide (inorganic iodide) is selected as the reaction catalyst; the preset reaction temperature is set to 80°C and the preset reaction time is set to 8h.

[0033] Specifically, this step involves adding SM1 (5.00 g, 1 eq), SM2 (12.97 g, 4 eq), and acetonitrile (25 ml, 5 v) to a 100 ml three-necked flask and stirring until the mixture is homogeneous. Then, sodium iodide (12.91 g, 4 eq) is added to the mixture, and the temperature is raised and refluxed at 80 °C for 8 hours.

[0034] S102. After the reaction is complete, the reaction solution is post-treated to obtain the target compound, which is tetrakis[(neovaleroxy)methyl]methylene diphosphonate (POM ester). The post-treatment includes the following steps: Water and MTBE were added to the reaction solution for extraction and separation to obtain the organic phase; The organic phase was washed sequentially with sodium sulfite solution and water, then subjected to desolvation under reduced pressure, and then distilled with n-heptane to obtain the crude target compound. n-Heptane was added to the crude target compound, and the crude target compound was then pulped, filtered, and dried.

[0035] The process of pulping, filtering, and drying the crude target compound includes: At 20℃~25℃, the crude product of the target compound is stirred and pulped until the stirring and pulping time reaches the first preset stirring time. The crude target compound is cooled until its temperature drops to 2°C to 8°C, and the crude target compound is stirred and pulped until the stirring and pulping time reaches the second preset stirring time. The crude product of the target compound was filtered, and the resulting filter cake was air-dried.

[0036] It is understood that in step S101, the reaction solution is reacted at a preset reaction temperature higher than room temperature. Therefore, in this step, after the reaction is completed, the present disclosure first cools the reaction solution to room temperature before proceeding with the post-processing steps.

[0037] Specifically, in this embodiment, after the reaction was completed, the reaction solution was cooled to room temperature, and 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture for extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then washed with 15 ml * 3 ml of purified water. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, and then 30 ml of n-heptane was added. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 4.66 g of white solid was obtained, which was tetrakis[(neovaleroxy)methyl]methylene diphosphonate, with a purity of 98.6% and a yield of 34.2%.

[0038] This disclosure utilizes an iodine-containing catalyst to replace the traditional strong acid catalyst, enabling efficient catalysis of the SM1 and SM2 reactions under mild conditions without the need for additional strong acid. The reaction system exhibits no strong corrosive effect on the reaction equipment, eliminating the need for special anti-corrosion treatment and reducing the investment cost of production equipment. Simultaneously, it avoids the large amounts of high-salt waste acid and wastewater generated by traditional processes, significantly reducing the discharge of waste gas, wastewater, and solid waste, thus better meeting the requirements of green production. Furthermore, the catalyst can be removed simply by water washing, eliminating the need for additional catalyst removal steps. Post-treatment only requires a single n-heptane slurry to obtain a high-purity product. Compared to traditional purification methods involving multiple recrystallizations or column chromatography, the process is significantly simplified, the operation is easier, and product loss during purification is reduced, further improving the final yield. It also reduces solvent consumption and production costs during purification, demonstrating promising prospects for industrial application.

[0039] Example 2

[0040] This embodiment provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate. The synthesis steps are the same as in Example 1. The difference from Example 1 is that in this embodiment, a mixed solution of acetonitrile and toluene is used as the organic solvent, potassium iodide (inorganic iodide) is used as the reaction catalyst, and the preset reaction time is set to 12h.

[0041] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), acetonitrile (25 ml, 5 v), and toluene (25 ml, 5 v) to a 100 ml three-necked flask and stir until well mixed. Add potassium iodide (14.3 g, 4 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0042] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 5.36 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.0% and a yield of 39.4%.

[0043] Example 3

[0044] This embodiment provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate, the synthesis steps of which are the same as those in the above embodiment. The difference is that in this embodiment, toluene is used as the organic solvent and iodide ketone (inorganic iodide) is used as the reaction catalyst; the preset reaction temperature is set to 110°C and the preset reaction time is set to 18h.

[0045] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (19.46 g, 6 eq), and toluene (50 ml, 10 v) to a 100 ml three-necked flask and stir until well mixed. Add cuprous iodide (20.51 g, 5 eq), start heating, and reflux at an internal temperature of 110 °C for 18 h.

[0046] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 3.89 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 98.9% and a yield of 28.6%.

[0047] Example 4

[0048] This embodiment provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate. The synthesis steps are the same as those in the above embodiment. The difference from Embodiment 1 is that in this embodiment, zinc iodide (inorganic iodide) is selected as the reaction catalyst, and the reaction time is set to 12h.

[0049] Furthermore, the present invention also discloses that the addition of at least a reaction catalyst for the reaction further includes the addition of a phase transfer catalyst to further accelerate the reaction process and improve the conversion rate. The phase transfer catalyst is any one of 12-crown-4, 15-crown-5, or 18-crown-6. In this embodiment, 12-crown-4 is selected as the phase transfer catalyst.

[0050] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (25 ml, 5 v) to a 100 ml three-necked flask and stir until well mixed. Add zinc iodide (27.5 g, 4 eq) and 12-crown-4 (0.04 g, 0.01 eq), and start heating. Maintain the internal temperature at 80 °C and reflux for 12 h.

[0051] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 6.21 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.2% and a yield of 45.6%.

[0052] Example 5

[0053] This embodiment provides a method for synthesizing tetra[(neovaleroxy)methyl]methylene diphosphonate, the synthesis steps of which are the same as those in Example 4. The difference from Example 4 is that in this embodiment, calcium iodide (inorganic iodide) is used as the reaction catalyst and 18-crown-6 is used as the phase transfer catalyst.

[0054] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (25.95 g, 8 eq), and acetonitrile (25 ml, 5 v) to a 100 ml three-necked flask and stir until well mixed. Add calcium iodide (25.32 g, 4 eq) and 18-crown-6 (0.06 g, 0.01 eq), and start heating. Maintain an internal temperature of 80 °C and reflux for 12 h.

[0055] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 6.30 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.2% and a yield of 46.3%.

[0056] Compared with Examples 1-3, Examples 4 and 5 further added a phase transfer catalyst to the reaction system. The results showed that the introduction of the phase transfer catalyst effectively promoted the mass transfer efficiency of the substrate between the two phases, and the product yield was significantly improved.

[0057] Example 6

[0058] This embodiment provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate. The synthesis steps are the same as in Example 1. The difference is that in this embodiment, an iodine-containing phosphonium salt iodide is used as the reaction catalyst, and the preset reaction time is set to 12 hours. The iodine-containing phosphonium salt iodide includes tetrabutylphosphonium iodide, triphenylmethylphosphonium iodide, tetraphenylphosphonium iodide, and tributyltetradecylphosphonium iodide. Specifically, in this embodiment, tetrabutylphosphonium iodide is used as the reaction catalyst.

[0059] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (25 ml, 5 v) to a 100 ml three-necked flask and stir until well mixed. Add tetrabutylphosphonium iodide (4.16 g, 0.5 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0060] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 10.01 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.3% and a yield of 73.5%.

[0061] Example 7

[0062] This embodiment provides a method for synthesizing tetra[(neovaleroxy)methyl]methylene diphosphonate. The synthesis steps are the same as in Example 1. The difference is that in this embodiment, a quaternary ammonium iodide is used as the reaction catalyst, and the preset reaction time is set to 12 hours. The quaternary ammonium iodide includes tetrabutylammonium iodide, tetraethylammonium iodide, tetramethylammonium iodide, benzyltriethylammonium iodide, trioctylmethylammonium iodide, hexadecyltrimethylammonium iodide, tetrahexylammonium iodide, and 1-methyl-1,4-diazabicyclo[2.2.2]octane-1-iodide. Specifically, tetrabutylammonium iodide is used as the reaction catalyst in this embodiment.

[0063] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (25 ml, 5 v) to a 100 ml three-necked flask and stir until well mixed. Add tetrabutylammonium iodide (3.97 g, 0.5 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0064] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 11.59 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.4% and a yield of 85.1%.

[0065] Example 8

[0066] This embodiment provides a method for synthesizing tetra[(neovaleroxy)methyl]methylene diphosphonate, the synthesis steps of which are the same as those in Example 7. The difference from Example 7 is that tetraethylammonium iodide (quaternary ammonium salt iodide) is used as the reaction catalyst in this embodiment, and the equivalent of the tetraethylammonium iodide is 0.2 eq.

[0067] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (20 ml, 4 v) to a 100 ml three-necked flask and stir until well mixed. Add tetraethylammonium iodide (1.1 g, 0.2 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0068] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 13.10 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.5% and a yield of 96.2%.

[0069] Example 9

[0070] This embodiment provides a method for synthesizing tetra[(neovaleroxy)methyl]methylene diphosphonate, the synthesis steps of which are the same as those in the above embodiment. The difference from embodiment 7 is that tetramethylammonium iodide (quaternary ammonium salt iodide) is used as the reaction catalyst in this embodiment.

[0071] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (20 ml, 4 v) to a 100 ml three-necked flask and stir until well mixed. Add tetramethylammonium iodide (0.86 g, 0.2 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0072] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 10.65 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 99.1% and a yield of 78.2%.

[0073] Example 10

[0074] This embodiment provides a method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate. The synthesis steps are the same as in Example 1. The difference is that in this embodiment, an imidazole iodide is used as the reaction catalyst, and the preset reaction time is set to 12 hours. The imidazole iodides include tetramethyl iodoureate, 1-ethyl-3-methylimidazolium iodide, and 1-hexyl-3-methylimidazolium iodide. Specifically, in this embodiment, 1-ethyl-3-methylimidazolium iodide is used as the reaction catalyst.

[0075] Based on the above settings, the specific steps for synthesizing tetrakis[(neopentyloxy)methyl]methylene diphosphonate in this embodiment are as follows: Add SM1 (5.00 g, 1 eq), SM2 (16.22 g, 5 eq), and acetonitrile (20 ml, 4 v) to a 100 ml three-necked flask and stir until well mixed. Add 1-ethyl-3-methylimidazolium iodide (1.02 g, 0.2 eq), start heating, and reflux at an internal temperature of 80 °C for 12 h.

[0076] After the reaction was complete, the reaction solution was cooled to room temperature. 25 ml of purified water and 25 ml of MTBE were added to the reaction mixture, followed by extraction and separation to obtain the organic phase. The organic phase was washed with 15 ml of 2% sodium sulfite solution, and then with 15 ml of purified water three times. The organic phase was desolvated under reduced pressure at 45°C. After no more dripping occurred, it was distilled with 10 ml of n-heptane, followed by the addition of 30 ml of n-heptane. The mixture was stirred and slurried at 20-25°C for 1 hour, then cooled to 2-8°C and stirred and slurried for 12 hours. The mixture was filtered, and the filter cake was allowed to air dry. 7.20 g of a white solid, tetrakis[(neovaleroxy)methyl]methylene diphosphonate, was obtained, with a purity of 98.3% and a yield of 52.9%.

[0077] The results from the above examples show that, under the same or similar reaction conditions, the catalytic performance of different types of iodine-containing catalysts varies significantly. When quaternary ammonium iodides are used as catalysts, the yield and purity of the target product are significantly better than those of other types of iodine-containing catalysts. Specifically, in Examples 7-9, when quaternary ammonium iodides were used, the yields reached 78.2%-96.2%, and the purity all exceeded 99.1%; while in Examples 1-3, when inorganic iodides were used, the yields were only 28.6%-39.4%, in Example 6, when iodine-containing phosphonium salts were used, the yield was 73.5%, and in Example 10, when imidazole iodides were used, the yield was 52.9%. The above comparisons fully demonstrate that the catalytic activity of quaternary ammonium iodides for this reaction is far higher than that of other types of iodine-based catalysts.

[0078] In quaternary ammonium iodides, the quaternary ammonium cations with different carbon chain lengths have a significant impact on catalytic efficiency. Example 7 showed a yield of 85.1%, Example 9 a yield of 78.2%, while Example 8, with only 0.2 equivalents of catalyst, achieved a yield of 96.2% and a purity of 99.5%, respectively 11 and 18 percentage points higher than the former two. This demonstrates that tetraethylammonium iodide exhibits the best catalytic effect, which is related to the moderate ethyl chain length, hydrophilic-hydrophobic balance, and optimal steric hindrance matching in its molecular structure, enabling it to most effectively promote the reaction between SM1 and SM2.

[0079] The various embodiments of this disclosure have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate, the method comprising: The substrate is dissolved or suspended in an organic solvent, and at least a reaction catalyst is added to carry out the reaction. The substrate is SM1 and SM2, the organic solvent is acetonitrile and / or toluene, and the reaction catalyst is an iodine-containing catalyst, which includes inorganic iodides, quaternary ammonium iodides, iodine-containing phosphorus iodides, and imidazole iodides. SM1 is a compound as shown in formula (I), and SM2 is a compound as shown in formula (II). ； ； After the reaction is complete, the reaction solution is post-treated to obtain the target compound, which is tetrakis[(neovaleroxy)methyl]methylene diphosphonate. The post-treatment includes the following steps: Water and MTBE were added to the reaction solution for extraction and separation to obtain the organic phase; The organic phase was washed sequentially with sodium sulfite solution and water, then subjected to desolvation under reduced pressure, and then distilled with n-heptane to obtain the crude target compound. n-Heptane was added to the crude target compound, and the crude target compound was then pulped, filtered, and dried.

2. The method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The reaction catalyst is a quaternary ammonium salt iodide, which includes tetrabutylammonium iodide, tetraethylammonium iodide, tetramethylammonium iodide, benzyltriethylammonium iodide, trioctylmethylammonium iodide, hexadecyltrimethylammonium iodide, tetrahexylammonium iodide and 1-methyl-1,4-diazabicyclo[2.2.2]octane-1-ammonium iodide.

3. The method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate according to claim 2, characterized in that, The reaction catalyst is tetraethylammonium iodide, and the equivalent of the tetraethylammonium iodide is 0.2 eq.

4. The method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The addition of at least a reaction catalyst for the reaction includes: Add the reaction catalyst and heat the reaction solution until the temperature of the reaction solution reaches the preset reaction temperature. The reaction solution is kept at the preset reaction temperature until the preset reaction time is reached.

5. The method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate according to claim 4, characterized in that, The preset reaction temperature is 80℃~110℃; the preset reaction time is 6h~24h.

6. The method for synthesizing tetrakis[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The process of pulping, filtering, and drying the crude target compound includes: At 20℃~25℃, the crude product of the target compound is stirred and pulped until the stirring and pulping time reaches the first preset stirring time. The crude target compound is cooled until its temperature drops to 2°C to 8°C, and the crude target compound is stirred and pulped until the stirring and pulping time reaches the second preset stirring time. The crude product of the target compound was filtered, and the resulting filter cake was air-dried.

7. The method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The addition of at least a reaction catalyst for the reaction also includes the addition of a phase transfer catalyst, wherein the phase transfer catalyst is any one of 12-crown-4, 15-crown-5, or 18-crown-6.

8. The method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The inorganic iodides include sodium iodide, potassium iodide, lithium iodide, calcium iodide, magnesium iodide, aluminum iodide, cuprous iodide, and zinc iodide; The iodine-containing phosphonium salt iodides include tetrabutylphosphonium iodide, triphenylmethylphosphonium iodide, tetraphenylphosphonium iodide, and tributyltetradecylphosphonium iodide; The imidazole iodides include tetramethyl iodoureate, 1-ethyl-3-methylimidazolium iodide, and 1-hexyl-3-methylimidazolium iodide.

9. The method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The equivalent of the reaction catalyst is 0.1 eq to 5 eq, and the equivalent of SM2 is 4 eq to 8 eq.

10. The method for synthesizing tetratetra[(neovaleroxy)methyl]methylene diphosphonate according to claim 1, characterized in that, The volume of the organic solvent is 4V~10V.

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