Process for the preparation of dimethyl hydroxymethyl phosphonate

Abstract

The present invention relates to a method for preparing diethyl hydroxymethylphosphonate in high purity by reacting diethyl phosphite with an aqueous formaldehyde solution in the presence of a base selected from sodium carbonate and potassium carbonate, wherein the amount of base is from 2 to 4 mol based on the amount of DEPI used.

Description

Background Technology

[0001] Diethyl hydroxymethylphosphonate (DEHMP, CAS No. 3084-40-0) is an organophosphorus compound used in a variety of industrial applications. For example, DEHMP is required to prepare the synthetic structural unit diethyl p-toluenesulfonyloxymethylphosphonate (DETMP, CAS No. 31618-90-3, see, for example, US 5,514,798). This, in turn, enables the synthesis of various pharmaceuticals, such as the antiviral active ingredients cidofovir, tenofovir, and adefovir, as well as their respective derivatives and prodrugs. Similar DEHMP derivatives have been proposed as herbicides (see, for example, EP 0 511 826 A2). Furthermore, DEHMP can be used to produce flame-retardant materials such as polyurethane (US 3,385,801), cotton fibers (US 3,726,639), or phenolic resins (DE 24 43 074 A1). DEHMP has also been proposed as a component of ashless lubricant formulations (WO 2016170707 A1).

[0002] For the synthesis of DEHMP, the reaction of diethyl phosphite (DEPI, CAS Registry No. 762-04-9) with formaldehyde is preferred in the prior art. However, under standard conditions, pure formaldehyde is a hazardous gas with a tendency to polymerize and is therefore preferably used in the reaction in the form of its solution or oligomers or polymers. Oligomers or polymers of formaldehyde, particularly paraformaldehyde (CAS Registry No. 30525-89-4), are in equilibrium with formaldehyde. Therefore, oligomers or polymers of formaldehyde, as well as formaldehyde solutions, are referred to as formaldehyde sources in the context of this invention and can be used as raw materials for the synthesis of DEHMP.

[0003] The synthesis of DEHMP from DEPI and formaldehyde sources requires a long reaction time of several days without additional catalyst (see US 2,494,862). Therefore, industrially feasible synthesis can only be carried out in the presence of a basic catalyst. Various methods for carrying out this synthesis are known, differing in the type of formaldehyde source, the type of basic catalyst, and the process conditions.

[0004] Among the various methods known for carrying out this synthesis, the first to be mentioned are those using paraformaldehyde as the formaldehyde source and trialkylamine as the base in pure form (see, for example, EP 0 511 826 A2) or in an organic solvent such as toluene (see, for example, US 5,514,798).

[0005] The first drawback of these methods is the use of paraformaldehyde as the formaldehyde source. Paraformaldehyde is industrially obtained from aqueous formaldehyde solutions by evaporation under reduced pressure. This step could be eliminated if DEHMP could be prepared directly from aqueous formaldehyde solutions. Furthermore, handling solid paraformaldehyde on an industrial scale is far more complex than handling liquid formaldehyde solutions in closed pipelines, in terms of occupational health and metrological techniques.

[0006] Furthermore, the high cost of trialkylamines in these methods necessitates their separation and recycling. Additionally, many trialkylamines are toxic; for example, triethylamine is toxic upon skin contact or if inhaled. Therefore, the use of such substances leads to undesirable additional costs for recycling and occupational safety measures, and may be undesirable due to potential contamination of reaction products.

[0007] Therefore, there has been a persistent effort to make the synthesis of DEHMP easier and more economically feasible by using aqueous formaldehyde solutions and cheaper bases. According to WO 2006003295 A1, DEPI reacts with aqueous formaldehyde in the presence of a metal hydroxide, an alkali metal monohydrogen phosphate, an alkali metal phosphate, or an alkali metal acetate. The amount of base to be used is specified as 1-100 mol% based on DEPI, preferably 5-20 mol%. In examples, bases between 10 and 80 mol% are used, where increasing the amount of base from 10 mol% to 80 mol% improves the yield. The base can be used in pure form or as an aqueous solution.

[0008] CN 109021011 A proposes the use of a combination of 37%-38% aqueous formaldehyde solution with sodium carbonate or potassium carbonate. The amount of these bases is claimed to be 5%-6% by weight based on the amount of formaldehyde solution. This corresponds to 5.0 to 6.5 mol% base based on the DEPI used, as can be understood from the given examples.

[0009] The method known from CN 109053799 A also uses an aqueous formaldehyde solution along with sodium carbonate or potassium carbonate. Based on the DEPI used, the amount of base should be 50 to 220 mol%, preferably 60 to 200 mol%. In this case, a phase transfer catalyst is also required, which should be a quaternary ammonium salt, polyethylene glycol, polyethylene glycol monomethyl ether, or polyethylene glycol dimethyl ether. Using a phase transfer catalyst is disadvantageous because it incurs additional costs and the catalyst must be separated from the product again.

[0010] CN 113121596 A discloses a very similar method in which DEPI reacts with an aqueous formaldehyde solution and sodium carbonate or potassium carbonate as a base in the presence of a phase transfer catalyst. The phase transfer catalyst used is tetrabutylammonium bromide. Regarding the total amount of base, the mass ratio of base to DEPI specified in CN 113121596 A results in a DEPI-based molar ratio of 17.5 to 23.8 mol% in the case of sodium carbonate and 13.4 to 18.3 mol% in the case of potassium carbonate.

[0011] Each reaction of DEPI with aqueous reagents or in aqueous solvents introduces the following problem: in addition to the desired reaction, DEPI undergoes hydrolysis to form monoethyl phosphite and ethanol. In particular, saponification of DEPI in alkaline media proceeds rapidly even at room temperature and produces a salt of monoethyl phosphite. For example, DE 24 56 627 A discloses the saponification of DEPI with a sodium hydroxide solution to form sodium monoethyl phosphite (CAS Registry No. 39148-16-8, referred to as “sodium O-ethylphosphonate” in DE 24 56 627 A). Sodium monoethyl phosphite exhibits fungicidal activity and is used to prepare the corresponding aluminum salt, which is also used as a fungicide (“aluminum triethylphosphonate”). According to DE 29 11 516 A, DEPI is saponified in a reaction mixture containing DEPI even at a weakly alkaline pH of 7.5 and at 75°C for one hour.

[0012] Saponification of DEPI during the synthesis of DEHMP is undesirable because it not only reduces the yield, but the resulting salts have proven destructive in various end uses, making removal necessary. Since these salts are not volatile, they are undetectable in GC analysis, meaning that the most common methods used to determine the composition of crude DEHMP are prone to error.

[0013] The purification of DEHMP faces considerable challenges under current technology. DEHMP is so volatile that overhead distillation requires extremely high temperatures and very low pressures (see example...). Org. Synth. [Organic Synthesis], Volume 7(Page 160, 1990). In industrial-scale production, this places very high demands on the equipment to be used. Yield losses due to secondary reactions are also unavoidable at high temperatures. The high polarity of DEHMP hinders its purification by extraction in an organic-aqueous solvent system. DEHMP is miscible with water in any ratio and is extremely hydrophilic. The measure of a substance's hydrophilicity is its octanol-water partition coefficient P, which describes the distribution of the substance in the n-octanol-water system. According to SciFinder, the octanol-water partition coefficient of DEHMP is estimated to be 0.13 (logP = -0.90 ± 0.36, modeled using ACD / Laboratory software V11.02). Since DEHMP is therefore more soluble in the aqueous phase than in the organic phase in a two-phase organic-aqueous solvent system, extraction in an organic-aqueous solvent system to remove water-soluble salts is extremely inefficient. Furthermore, according to existing technology, problematic solvents, such as chloroform, which is toxic and potentially carcinogenic, are used for this purpose (see CN103073747 A). Summary of the Invention

[0014] Therefore, the object of the present invention is to provide a method for preparing DEHMP that completely or partially avoids the aforementioned disadvantages of the prior art. Preferably, the method should use a cost-effective, toxicologically safe catalyst and achieve higher product purity than methods from the prior art, even prior to purification.

[0015] Surprisingly, it has been found that by using certain inorganic bases in a specific amount in the reaction of DEPI with an aqueous formaldehyde solution, DEHMP can be produced in high purity. Comparative experiments show that, even without complex purification procedures, the purity of DEHMP obtained in this way is much higher than that obtained by known methods.

[0016] The present invention provides a method for preparing DEHMP by reacting DEPI with an aqueous formaldehyde solution, characterized in that the reaction is carried out in the presence of a base selected from the group consisting of sodium carbonate and potassium carbonate, wherein the amount of the base is from 2 to 4 mol based on the amount of DEPI used.

[0017] The formaldehyde aqueous solution has a formaldehyde concentration of 10% to 60% by weight. Preferably, the concentration is 20% to 50% by weight, and particularly preferably 30% to 40% by weight. In addition to water, formaldehyde, and known hydrated oligomers and polymers thereof, the formaldehyde aqueous solution may also contain other components, such as methanol. Furthermore, the formaldehyde aqueous solution may contain solid particles composed of formaldehyde oligomers and polymers. The formaldehyde aqueous solution is optionally diluted reaction product of industrially operated methanol oxidation. Alternatively, the solution can be prepared by dissolving a formaldehyde-forming substance (such as paraformaldehyde or 1,3,5-trioxane) in water.

[0018] The molar ratio of formaldehyde to DEPI can vary between 1.0 and 2.0, and is preferably between 1.0 and 1.2. Particularly preferably, 1.0 to 1.1 mol of formaldehyde is used per mol of DEPI.

[0019] Sodium carbonate and potassium carbonate, used as bases, are used alone or as mixtures of various bases. It is preferred to use only one of the mentioned bases alone. Sodium carbonate is particularly preferred.

[0020] These bases can be used in the method as an anhydrous solid, a solid containing water of crystallization, or as an aqueous solution. The use of an aqueous solution is preferred. The concentration of the base in the aqueous solution is, in each case, from 5% to 60% by weight of the anhydrous base, preferably from 10% to 50% by weight, and particularly preferably from 15% to 40% by weight.

[0021] The amount of one or more bases to be used in this method is from 2 to 4 mol% based on the amount of DEPI used. This molar ratio is calculated based on the amount of anhydrous base, regardless of whether the base is used in anhydrous or aqueous form. It is preferred to use 2.0 to 3.8 mol% base, and particularly preferred to use 2.3 to 3.7 mol% base.

[0022] The method according to the invention is carried out by contacting the mentioned raw materials with each other in a suitable reactor at a temperature of 5°C to 85°C. This is preferably carried out under mixing conditions. The method is preferably carried out at 15°C to 75°C; particularly preferably, the method is carried out at 25°C to 65°C. The required residence time at the selected reaction temperature can be easily determined based on reducing the heat of reaction or by analytical methods. Suitable analytical methods include, for example, gas chromatography, high-performance liquid chromatography, or NMR spectroscopy.

[0023] The raw materials can be initially charged into the reactor together or metered into the reactor sequentially in any desired order. In a preferred variant of the method, an aqueous formaldehyde solution is initially charged and DEPI is metered in. The alkali can initially be charged with paraformaldehyde, or subsequently metered in alone or with diethyl phosphite. Preferably, the alkali is charged initially.

[0024] Preferably, the reaction is carried out until 90% or more of the diethyl phosphite used is converted to diethyl hydroxymethylphosphonate. The conversion rate can be determined by... 31 Determined by P NMR spectroscopy.

[0025] Preferably, the reaction is carried out until the desired reaction is achieved. 31 The residual content of diethyl phosphite in the reaction mixture, as determined by P NMR spectroscopy, is less than 2%, preferably less than 1%.

[0026] This method can be performed in batches or continuously. In batch processes, for example, conventional stirred tanks can be used. For continuous processes, cascading stirred tanks is an option.

[0027] In addition to synthesis, the method according to the invention may also include post-processing steps and separation operations known from the prior art. Examples of these include filtration, membrane technology, ion exchange, extraction, adsorption, or optionally distillation under reduced pressure. Preferably, post-reaction purification does not include any extraction of diethyl hydroxymethylphosphonate from the aqueous phase with organic solvents.

[0028] In a preferred embodiment of the method, after synthesis, water present in the reaction mixture is removed by a suitable separation operation to a residual content of 1% or less by weight, particularly preferably 0.5% or less by weight.

[0029] The method according to the invention enables the simple acquisition of compositions containing phosphorus components, which consist of diethyl hydroxymethylphosphonate to a degree of at least 90 mol%, with minimal use of raw materials.

[0030] The phosphorus-containing component of the composition, consisting of diethyl hydroxymethylphosphonate (at least 90 mol%) and diethyl phosphite (at less than 2%, preferably less than 1%), can be obtained by the method according to the invention without any complex purification after the reaction.

[0031] Surprisingly, such compositions have been found to be advantageous for applications in which impurities (such as byproducts, starting materials, and basic catalysts) appearing in the reaction mixture during synthesis according to the prior art hinder direct use in application and thus require complex purification steps, such as for use as flame retardant additives in plastics added even before or during polymerization.

[0032] Therefore, the present invention also provides the above-described compositions. Detailed Implementation

[0033] The following examples illustrate the invention in more detail, but none of them should limit the intent of the invention.

[0034] Example

[0035] pass 31 The composition of phosphorus-containing components in the reaction mixture was determined by P NMR spectroscopy. The phosphorus-containing components were determined using Spinsolver from the manufacturer Magritek. TM NMR measurements were performed at a measurement frequency of 32.4 MHz on an 80 phosphorus spectrometer. Measurements were taken from an undiluted sample of the reaction mixture. The signals for DEHMP and DEPI were assigned using the spectra of the truly pure sample. In addition to the signals of the two components mentioned, other signals were always observed in the reaction mixture; however, these signals could not be reliably assigned to any compound. Quantification was performed using proton decoupling spectroscopy. Assuming no loss of phosphorus-containing components from the reaction mixture during the reaction time, the integral sum of all signals corresponds to 100 mol% of phosphorus present in the DEPI used. Therefore, the yield of DEPI was obtained directly from the proportion of DEHMP, and the conversion from the proportion of DEPI.

[0036] Sodium carbonate and potassium carbonate were obtained as anhydrous products from VWR International GmbH and dried in a drying oven at 120°C for 16 h prior to the experiment. DEPI used was a commercial product from Lanxess Deutschland GmbH. A 37% aqueous formaldehyde solution was obtained from Acros. The comparative sample for DEHMP was obtained from Sigma-Aldrich.

[0037] Comparison Example 1 (Not of this invention)

[0038] Initially, 47.3 g of a 37% formaldehyde aqueous solution and 4.2 g (0.039 mol, 6.8 mol% relative to DEPI) of sodium carbonate were placed in a 250 ml four-necked flask equipped with a heating jacket, thermometer, mechanical stirrer, dropping funnel, and reflux condenser and heated to 60°C. 80.0 g (0.58 mol) of DEPI was added dropwise through the dropping funnel with stirring. The resulting reaction mixture was stirred at 60°C for 2 h. After cooling and filtration, the mixture was... 31P NMR determined the phosphorus-containing composition to be: 83.0 mol% DEHMP, 0.0 mol% DEPI, and 17.0 mol% unknown byproducts.

[0039] Comparison Example 2 (Not of this invention)

[0040] Initially, 47.3 g of a 37% formaldehyde aqueous solution and 4.05 g (0.030 mol, 5.1 mol% relative to DEPI) of potassium carbonate were placed in a 250 ml four-necked flask equipped with a heating jacket, thermometer, mechanical stirrer, dropping funnel, and reflux condenser and heated to 35°C. 80.0 g (0.58 mol) of DEPI was added dropwise through the dropping funnel with stirring. The resulting reaction mixture was stirred at 60°C for 2 h. After cooling and filtration, the mixture was... 31 P NMR determined the phosphorus-containing composition to be: 89.7 mol% DEHMP, 0.0 mol% DEPI, and 10.3 mol% unknown byproducts.

[0041] Comparison Example 3 (Not of this invention)

[0042] Initially, 373.8 g of a 32% formaldehyde aqueous solution and 5.99 g (0.057 mol, 1.5 mol% relative to DEPI) of sodium carbonate were charged into a 1000 ml four-necked flask equipped with a heating jacket, thermometer, mechanical stirrer, dropping funnel, and reflux condenser and heated to 45°C. 528.0 g (3.82 mol) of DEPI was added dropwise through the dropping funnel with stirring. The resulting reaction mixture was heated to 60°C after 1 h and then stirred at 60°C for 2 h. After cooling and filtration, the mixture was... 31 PNMR determined the phosphorus-containing composition to be: 89.0 mol% DEHMP, 2.6 mol% DEPI, and 8.4 mol% unknown byproducts.

[0043] Example 1

[0044] Initially, 189.2 g of a 37% formaldehyde aqueous solution and 60.12 g (0.085 mol, 3.7 mol% relative to DEPI) of a 15% sodium carbonate aqueous solution were charged into a 1000 ml glass reactor with a flat flange ground joint (which had a glass jacket that could be heated by a thermostat and was equipped with a thermometer, mechanical stirrer, metering pump, and reflux condenser) and heated to 60°C. 320.0 g (2.32 mol) of DEPI was metered in. The resulting reaction mixture was stirred at 60°C for 2 h. After cooling and filtration, the reaction mixture was sampled and analyzed by…31 P NMR determined the composition of the phosphorus-containing component to be: 91.6 mol% DEHMP, 0.0 mol% DEPI, and 8.4 mol% unknown byproducts.

[0045] Example 2

[0046] Initially, 189.2 g of a 37% formaldehyde aqueous solution and 46.0 g (0.065 mol, 2.8 mol% relative to DEPI) of a 15% sodium carbonate aqueous solution were charged into a 1000 ml glass reactor with a flat flange ground joint (which had a glass jacket that could be heated by a thermostat and was equipped with a thermometer, mechanical stirrer, metering pump, and reflux condenser) and heated to 35°C. 320.0 g (2.32 mol) of DEPI was metered in. The resulting reaction mixture was stirred at 35°C for 8 h. After cooling and filtration, the reaction mixture was sampled and analyzed by… 31 P NMR determined its composition to be: 91.7 mol% DEHMP, 0.7 mol% DEPI, and 7.6 mol% unknown byproducts.

[0047] evaluate

[0048] Compare Examples 1 and 2 to the methods known from CN 109021011 A. 31 P NMR analysis indicated the formation of a considerable amount of unidentified byproducts. Therefore, the DEHMP yield remained below 90%.

[0049] In contrast, in the embodiments according to the invention, a significantly better DEHMP yield of over 90% was achieved under comparable reaction conditions using a specific combination of base and a reduction in the amount relative to DEPI. Surprisingly, not only was base saved, but a better yield was also achieved.

Claims

1. A method for preparing diethyl hydroxymethylphosphonate by reacting diethyl phosphite with an aqueous formaldehyde solution, characterized in that, The reaction is carried out in the presence of at least one base selected from the group consisting of sodium carbonate and potassium carbonate, the amount of which is from 2 to 4 mol based on the amount of DEPI used.

2. The method according to claim 1, characterized in that, The formaldehyde concentration of the aqueous formaldehyde solution is from 10% to 60% by weight, preferably from 20% to 50% by weight, and particularly preferably from 30% to 40% by weight.

3. The method according to one or more of claims 1 and 2, characterized in that, The amount of the formaldehyde aqueous solution, taking into account its formaldehyde content, corresponds to 1.0 to 2.0, preferably 1.0 to 1.2 mol, and particularly preferably 1.0 to 1.1 mol based on 1 mol of diethyl phosphite.

4. The method according to one or more of claims 1 to 3, characterized in that, Sodium carbonate is used as the base.

5. The method according to one or more of claims 1 to 4, characterized in that, The alkali is used in the form of an aqueous solution with a concentration of 5% to 60% by weight of anhydrous alkali, preferably 10% to 50% by weight, and particularly preferably 15% to 40% by weight.

6. The method according to one or more of claims 1 to 5, characterized in that, The amount of the base used is from 2.0 to 3.8 mol% in each case, preferably from 2.3 to 3.7 mol%, based on the amount of DEPI used.

7. The method according to one or more of claims 1 to 6, characterized in that, The method is carried out at a reaction temperature ranging from 5°C to 85°C, preferably from 15°C to 75°C, and particularly preferably from 25°C to 65°C.

8. The method according to one or more of claims 1 to 7, characterized in that, The formaldehyde aqueous solution was initially loaded into the reactor, and diethyl phosphite was added in a measured amount.

9. The method according to one or more of claims 1 to 8, characterized in that, Initially, the formaldehyde aqueous solution and the alkali were loaded into the reactor, and diethyl phosphite was added in a metered manner.

10. The method according to one or more of claims 1 to 9, characterized in that, After the reaction, water is completely or partially removed by distillation.

11. The method according to one or more of claims 1 to 10, characterized in that, The reaction proceeds until it passes through 31 90% or more of the diethyl phosphite used, as determined by P NMR spectroscopy, was converted to diethyl hydroxymethylphosphonate.

12. The method according to one or more of claims 1 to 11, characterized in that, The reaction proceeds until it passes through 31 The residual content of diethyl phosphite in the reaction mixture, as determined by P NMR spectroscopy, is less than 2%, preferably less than 1%.

13. The method according to one or more of claims 1 to 12, characterized in that, Following the reaction, the diethyl hydroxymethylphosphonate was not purified by extraction from the aqueous phase with an organic solvent.

14. The method according to one or more of claims 1 to 13, characterized in that, The amount of one or more bases to be used in this method is from 2 to 4 mol based on the amount of DEPI used.