Process for the preparation of dimethyl hydroxymethyl phosphonate

Abstract

The present invention relates to a process for the preparation of high purity diethyl hydroxymethyl phosphonate by reacting diethyl phosphite with paraformaldehyde in the presence of 1 to 3 mol% of sodium carbonate.

Description

[0001] Diethyl hydroxymethylphosphonate (DEHMP, CAS No. 3084-40-0) is an organophosphorus compound used in various industrial applications. Therefore, DEHMP is needed to prepare the synthetic building block 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, and their corresponding derivatives and prodrugs. Similar DEHMP derivatives have been proposed for use as herbicides (see, for example, EP 0 511 826 A2). Additionally, DEHMP can be used to prepare fire-retardant materials, such as polyurethane (US 3,385,801), cotton fibers (US 3,726,639), or phenolic resins (DE 24 43074 A1). DEHMP has also been proposed as a component of ashless lubricant formulations (WO 2016170707 A1).

[0002] To synthesize DEHMP, diethyl phosphite (DEPI, CAS No. 762-04-9) is preferably reacted with paraformaldehyde in the prior art. When this reaction is carried out without an additional catalyst, it requires a long reaction time of many days (see US 2,494,862). Therefore, the only technically feasible synthetic scheme is that it is carried out in the presence of a base. For this synthesis, trialkylamines, in their physical form (see, for example, EP 0 511 826 A2) or in organic solvents (e.g., toluene, see, for example, US 5,514,798), are industrially preferred as the base. The disadvantages of these methods are the high cost of trialkylamines and the resulting high costs of their separation and recycling. Furthermore, many trialkylamines are toxic; for example, triethylamine is toxic upon skin contact or inhalation. The use of such substances results in undesirable high costs for workplace protective measures and may be undesirable due to potential contamination of the reaction products.

[0003] Inorganic bases have been proposed as alternatives to trialkylamines. CN 103073747 A also discloses the synthesis of DEHMP from DEPI and paraformaldehyde in the presence of a catalyst. Various inorganic acids, neutral salts, and bases, as well as different organic amine bases, are claimed as catalysts. The required catalyst amount is given as 1-20 mol% relative to the amount of DEPI used. In several examples using an inorganic base, potassium carbonate was used at 5 mol% relative to the amount of DEPI used. The product was purified by chloroform extraction.

[0004] According to CN 105541910 A, DEHMP was prepared in a solvent from DEPI and paraformaldehyde using potassium carbonate, sodium carbonate, or triethylamine as a base, wherein potassium carbonate is preferred and yields a higher yield. The required amount of base is not given; in the examples, 3.3 mol% potassium carbonate or 4.3 mol% sodium carbonate was used, with the higher yield achieved using potassium carbonate in a total of two reaction steps.

[0005] CN 106699814 A discloses the synthesis of DEHMP from DEPI and paraformaldehyde in toluene as a solvent, in the presence of 318 mol% excess potassium carbonate as a base.

[0006] DEHMP is known from EP 3 719 047 A1 to be prepared in a solvent from DEPI and paraformaldehyde in the presence of 5 mol% potassium carbonate.

[0007] None of the cited literature on the synthesis of DEHMP using inorganic bases such as potassium carbonate provides conversion rates and selectivity.

[0008] The use of basic catalysts in the preparation of DEHMP always comes with the following disadvantage: the direct reaction products contain significant residual amounts of the base or its salts as subsequent products. If these residues interfere with the subsequent use of DEHMP, they must be separated in a purification step.

[0009] However, according to existing techniques, the purification of DEHMP is associated with significant challenges. DEHMP's volatility is so low that top distillation requires extremely high temperatures and very low pressures (see, for example...). Organic Synthesis (Org. Synth.), Collected Works Volume 7 (Page 160, 1990). This places very high demands on the equipment used in large-scale production. The high polarity of DEHMP makes purification via extraction in an organic-aqueous solvent system more difficult. DEHMP is miscible with water in any ratio and is highly hydrophilic. The measure of a substance's hydrophilicity is its octanol-water partition coefficient P, which describes the distribution of the substance in an 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 / Labs software V11.02). Because DEHMP is therefore distributed more in the aqueous phase than the organic phase, extraction in organic-aqueous solvent systems used for separating water-soluble salts is very inefficient. Furthermore, problematic solvents, such as the toxic and potentially carcinogenic chloroform, are used for this purpose according to existing techniques (see CN103073747 A).

[0010] CN 105 541 910 A discloses the preparation of DEHMP using 3.3 mol% potassium carbonate or 4.3 mol% sodium carbonate, but the yield is less than 90%.

[0011] The object of this invention is therefore to provide a method for preparing DEHMP that completely or partially avoids the aforementioned disadvantages of the prior art. Preferably, this method uses a low-cost, toxicologically harmless catalyst and achieves higher product purity than prior art methods prior to purification.

[0012] Surprisingly, it has been found that when the reaction of DEPI with paraformaldehyde is carried out in the presence of sodium carbonate in combination with a specific amount of this catalyst, ranging from 1 to 3 mol%, preferably 2 to 3 mol% (relative to the amount of DEPI used), DEHMP can be prepared with high purity. Comparative experiments show that DEHMP is obtained with significantly higher purity even without costly purification procedures.

[0013] The subject of this invention is a method for preparing DEHMP by reacting DEPI with paraformaldehyde, characterized in that the reaction is carried out in the presence of sodium carbonate in an amount of 1 to 3 mol%, preferably 2 to 3 mol%, relative to the amount of DEPI used.

[0014] The reaction can be carried out in an organic solvent. Solvents in which the starting material can be at least partially dissolved are suitable as organic solvents. Here, those skilled in the art understand "partially soluble" to mean a solubility of at least 10 g, preferably at least 100 g, and particularly preferably at least 250 g per liter of solvent at a temperature of 40°C. The solvent typically contains less than 5% by weight of water, preferably less than 1% by weight, and particularly preferably less than 0.2% by weight of water.

[0015] Examples of suitable solvents are alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, or DEHMP), hydrocarbons (e.g., toluene, xylene, cyclohexane, or n-heptane), halogenated hydrocarbons (e.g., dichloromethane or chlorobutane), ethers (e.g., diethyl ether or methyl tert-butyl ether), and esters (e.g., ethyl acetate, n-butyl acetate, triethyl phosphate), as well as mixtures of these substances.

[0016] Ethanol is preferred as a solvent.

[0017] Sodium carbonate is either anhydrous or contains water of crystallization. Anhydrous sodium carbonate (CAS No. 497-19-8) is preferred.

[0018] The amount of sodium carbonate used in this method is 1 to 3 mol% relative to the amount of DEPI used. Preferably, 2 to 3 mol% and particularly preferably 2.4 to 3.0 mol% sodium carbonate is used.

[0019] The method of the present invention is carried out in such a manner that the above-mentioned raw materials and solvent are brought into contact with each other by thorough mixing in a suitable reactor at a temperature of 5 to 75°C, and thus a reaction is carried out. Preferably, the method is carried out at 15 to 65°C, and particularly preferably at 25 to 55°C. It has been shown that the lower reaction temperature in the present method compared to the prior art produces a surprising advantage in terms of conversion. The required residence time at the selected reaction temperature can be easily determined by means of the decaying heat of reaction. Alternatively, the conversion of the raw materials in the reaction mixture can be obtained by means of analytical methods. Suitable analytical methods include, for example, gas chromatography, high-performance liquid chromatography, or NMR spectroscopy.

[0020] The raw materials can be pre-placed together in the reactor or metered into the reactor sequentially in any order. In a preferred variant of this method, paraformaldehyde and optionally a solvent are pre-placed, followed by metered addition of diethyl phosphite. Sodium carbonate can be pre-placed together with paraformaldehyde and optionally a solvent, or subsequently metered in alone or with diethyl phosphite. Pre-placement of sodium carbonate is preferred.

[0021] Preferably, the reaction is carried out until 90% or more of the diethyl phosphite used has been converted to diethyl hydroxymethylphosphonate. This can be achieved by means of... 31 P-NMR spectroscopy was used to determine the conversion rate.

[0022] Preferably, the reaction is carried out until... 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%.

[0023] This method can be carried out in batches or continuously. When carried out in batches, for example, a common stirred tank can be used. For continuous operation, cascaded stirred tanks, for example, are advantageous.

[0024] Following synthesis, the method according to the invention may further include additional processing steps and purification operations known from the prior art. Examples include filtration, membrane technology, ion exchange, extraction, adsorption, or distillation (optionally under reduced pressure). This purification preferably does not include extraction after the reaction, and in particular, does not include purification by adding water and extracting diethyl hydroxymethylphosphonate from the aqueous phase with an organic solvent.

[0025] More preferably, the solvent is at least partially separated by distillation after the reaction. In another preferred embodiment of the method, volatile substances, especially excess feedstock and / or optionally used solvent, contained in the reaction mixture are separated by suitable separation operations after synthesis to a residual content of 1% by weight or less, particularly preferably 0.5% by weight or less. A combined treatment, including filtration and separation of volatile substances by distillation or stripping, is particularly preferred.

[0026] The method according to the invention can achieve, in a simple manner and with minimal raw material usage, a composition comprising at least 90 mol% of diethyl hydroxymethylphosphonate as its phosphorus component.

[0027] The method according to the invention can also yield a composition without costly purification after the reaction, wherein the phosphorus-containing component of the composition comprises at least 90 mol% diethyl hydroxymethylphosphonate and less than 2%, preferably less than 1%, diethyl phosphite.

[0028] It has been surprisingly determined that such compositions are advantageously used in applications where impurities (such as byproducts, starting materials and catalysts) generated in the reaction mixture according to existing synthetic schemes are prevented from being used directly in the application, thus requiring costly purification steps (e.g., when used in plastics as a fire retardant additive that has already been added before or during polymerization).

[0029] Therefore, the above-described composition is also the subject of this invention.

[0030] The invention is illustrated in detail by way of the following embodiments, but should not be construed as limiting the invention thereon.

[0031] Example

[0032] With the help of 31 The composition of the reaction mixture was obtained by P-NMR spectroscopy. NMR measurements were performed on a Spinsolver manufactured by Magritek. TMMeasurements were performed at a frequency of 32.4 MHz on an 80 phosphorus spectrometer. The reaction mixture was measured in its undiluted state. The signals of DEHMP and DEPI were correlated with the original pure samples using spectral analysis. In addition to the signals of these two components, other signals were consistently observed in the reaction mixture; however, these other signals could not be reliably correlated with any compound. Proton decoupling spectroscopy was used for quantification. Assuming no loss of phosphorus-containing components during the reaction duration, the integral sum of all signals corresponds to 100 mol% of phosphorus contained in the DEPI used. That is, the yield relative to DEPI was directly derived from the proportion of DEHMP, and the conversion was derived from the proportion of DEPI.

[0033] Ethanol contained less than 0.1% by weight of water. Toluene was dried via molecular sieves. All bases used were obtained as anhydrous products from VWR International GmbH and dried in a drying oven at 120°C for 16 hours prior to the experiment. DEPI used was a commercially available product from Lanxess Deutschland GmbH. Paraformaldehyde was obtained from Fisher Scientific GmbH.

[0034] Comparative Example 1 (Not this invention)

[0035] In a 250 ml three-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, and reflux condenser, 80 ml of ethanol, 4.00 g (0.029 mol, 5.0 mol% relative to DEPI), 17.4 g of paraformaldehyde, and 80.0 g (0.58 mol) of DEPI were mixed together at 35°C. The resulting reaction mixture was stirred at 35°C for 2 hours and then at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a [missing information - likely a specific method or technique]. 31 P-NMR determined its composition to be: 81.8 mol% DEHMP, 4.6 mol% DEPI, and 13.6 mol% unknown byproducts.

[0036] Comparative Example 2 (Not this invention)

[0037] In a 250 ml three-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, and reflux condenser, 63 ml of ethanol, 2.00 g (0.014 mol, 2.5 mol% relative to DEPI), 19.0 g of paraformaldehyde, and 80.0 g (0.58 mol) of DEPI were mixed together at 35°C. The resulting reaction mixture was stirred at 35°C for 2 hours and then at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a [missing information - likely a device or apparatus]. 31 P-NMR determined its composition to be: 78.8 mol% DEHMP, 13.1 mol% DEPI, and 8.1 mol% unknown byproducts.

[0038] Comparative Example 3 (Not this invention)

[0039] The reaction mixture was prepared in the same manner as in Comparative Example 2, except that 1.07 g of potassium carbonate was replaced with lithium carbonate. According to... 31 The composition of the P-NMR was: 4.3 mol% DEHMP, 94.8 mol% DEPI, and 0.9 mol% unknown byproducts.

[0040] Comparative Example 4 (Not this invention)

[0041] The reaction mixture was prepared in the same manner as in Comparative Example 2, except that 0.82 g of potassium carbonate was replaced with calcium oxide. According to... 31 The composition of the P-NMR was: 49.8 mol% DEHMP, 43.6 mol% DEPI, and 6.6 mol% unknown byproducts.

[0042] Comparative Example 5 (Not this invention)

[0043] The reaction mixture was prepared in the same manner as in Comparative Example 2, except that 1.08 g of potassium carbonate was replaced with calcium hydroxide. According to... 31 The composition of the P-NMR was: 56.5 mol% DEHMP, 34.1 mol% DEPI, and 9.4 mol% unknown byproducts.

[0044] Comparative Example 6 (Not this invention)

[0045] 41.0 g of paraformaldehyde and 138.1 g of DEPI were pre-placed in a 250 ml three-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, and reflux condenser. The resulting reaction mixture was heated to 85°C over 40 minutes and then stirred at 85°C for 3 hours. The sample of the reaction mixture at this point... 31P-NMR analysis showed a residual DEPI content of 41.9 mol%. The reaction mixture was stirred at 85°C for 2 hours, and then... 31 P-NMR still yielded 12.9 mol% residual DEPI. Stirring was continued at 85°C for 4 hours, followed by cooling and filtration using... 31 P-NMR determined the composition of the crude product to be: 35.6 mol% DEHMP, 3.8 mol% DEPI, and 60.7 mol% unknown byproducts.

[0046] Comparative Example 7 (not the present invention, but corresponding to Example 2 in CN 105 541 910 A)

[0047] In a 250 ml three-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 30.0 g (0.22 mol) DEPI, 30 ml isopropanol, 1.0 g (7.2 mmol, 3.3 mol% relative to DEPI) potassium carbonate, and 7.8 g paraformaldehyde were successively pre-placed and heated to 86°C with stirring. The resulting reaction mixture was continued to be stirred at 86°C, and samples were periodically extracted. These samples were filtered separately and subjected to [further action / method / treatment]. 31 The phosphorus-containing components were analyzed by P-NMR spectroscopy. The reaction was stopped when less than 0.2 mol% DEPI was detected. The phosphorus-containing components of the reaction mixture consisted of 86.8 mol% DEHMP, 0.0 mol% DEPI, and 13.2 mol% unknown byproducts.

[0048] Comparative Example 8 (not the present invention, but corresponding to Example 5 in CN 105 541 910 A)

[0049] In a 250 ml three-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 30.0 g (0.22 mol) DEPI, 30 ml isopropanol, 1.0 g (9.4 mmol, 4.3 mol% relative to DEPI) sodium carbonate, and 7.5 g paraformaldehyde were successively pre-placed and heated to 80°C with stirring. The resulting reaction mixture was continued to be stirred at 80°C, and samples were periodically extracted. These samples were filtered separately and subjected to [further action / method / treatment]. 31 The phosphorus-containing components were analyzed by P-NMR spectroscopy. The reaction was stopped when less than 0.2 mol% DEPI was detected. The phosphorus-containing components of the reaction mixture consisted of 89.3 mol% DEHMP, 0.0 mol% DEPI, and 10.7 mol% unknown byproducts.

[0050] Example 1

[0051] In a 250 ml four-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, and reflux condenser, 63 ml of ethanol, 1.55 g (0.015 mol, 2.5 mol% relative to DEPI), 19.0 g of paraformaldehyde, and 80.0 g (0.58 mol) of DEPI were mixed together at 35°C. The resulting reaction mixture was stirred at 35°C for 2 hours and then at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a [missing information - likely a device or apparatus]. 31 P-NMR determined the composition of the phosphorus-containing component to be: 92.2 mol% DEHMP, 0.4 mol% DEPI, and 7.4 mol% unknown byproducts.

[0052] Example 2

[0053] In a 2000 ml four-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 316 ml of ethanol, 7.75 g (0.073 mol, 2.5 mol% relative to DEPI), and 95.0 g of paraformaldehyde were pre-placed and heated to 35°C. Over 2 hours, 400.0 g (2.90 mol) of DEPI was added dropwise from the dropping funnel at 35°C. The resulting reaction mixture was heated to 60°C and stirred at 60°C for 4 hours. After cooling and filtration, a sample was extracted from the reaction mixture using a [missing information - likely a specific method or technique]. 31 P-NMR determined the composition of the phosphorus-containing component to be: 91.4 mol% DEHMP, 0.6 mol% DEPI, and 8.0 mol% unknown byproducts.

[0054] Volatile components were removed from the reaction mixture using a rotary evaporator at 60°C and 10 mbar. 480.4 g of a colorless, clear liquid was obtained. According to... 31 The composition of the phosphorus-containing component of P-NMR is as follows: 91.1 mol% DEHMP, 0.2 mol% DEPI, and 8.7 mol% unknown byproducts.

[0055] Example 3

[0056] A 250 ml four-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler was pre-filled with 63 ml of ethanol, 1.55 g (0.015 mol, 2.5 mol% relative to DEPI), and 19.0 g of paraformaldehyde and heated to 60°C. 80.0 g (0.58 mol) of DEPI was added dropwise from the dropping funnel at 60°C over 2 hours. The resulting reaction mixture was stirred at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a... 31 P-NMR determined the composition of the phosphorus-containing component to be: 92.1 mol% DEHMP, 0.5 mol% DEPI, and 7.4 mol% unknown byproducts.

[0057] Example 4

[0058] In a 250 ml four-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 35 ml of ethanol, 1.55 g (0.015 mol, 2.5 mol% relative to DEPI), and 19.0 g of paraformaldehyde were pre-placed and heated to 60°C. Over 2 hours, 80.0 g (0.58 mol) of DEPI was added dropwise from the dropping funnel at 60°C. The resulting reaction mixture was stirred at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a [missing information - likely a specific method or technique]. 31 P-NMR determined the composition of the phosphorus-containing component to be: 92.2 mol% DEHMP, 0.0 mol% DEPI, and 7.8 mol% unknown byproducts.

[0059] Example 5

[0060] The reaction mixture was prepared in the same manner as in Example 3, except that the amount of sodium carbonate used was 1.85 g (0.017 mol, 3.0 mol% relative to DEPI). According to... 31 The composition of the phosphorus-containing component of P-NMR is as follows: 91.9 mol% DEHMP, 0.0 mol% DEPI, and 8.1 mol% unknown byproducts.

[0061] Example 6

[0062] In a 1000 ml flat-faced ground glass reactor with a thermostat-heatable glass sleeve and equipped with a thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 461 ml of ethanol, 5.86 g (0.055 mol, 2.4 mol% relative to DEPI), and 74.8 g of paraformaldehyde were pre-placed and heated to 60°C. 323.5 g (2.43 mol) of DEPI was added dropwise over 2 hours at 60°C via the dropping funnel. The resulting reaction mixture was stirred at 60°C for 4 hours. After cooling and filtration, a sample was extracted from the reaction mixture using a thermometer, mechanical stirrer, dropping funnel, and reflux cooler. 31 P-NMR determined the composition of the phosphorus-containing component to be: 91.1 mol% DEHMP, 0.9 mol% DEPI, and 8.0 mol% unknown byproducts.

[0063] Example 7

[0064] In a 250 ml four-necked flask equipped with a heating mantle, thermometer, mechanical stirrer, dropping funnel, and reflux cooler, 25 g toluene, 25 g ethanol, 1.55 g (0.015 mol, 2.5 mol% relative to DEPI) sodium carbonate, and 19.0 g paraformaldehyde were pre-placed and heated to 35°C. Over 2 hours, 80.0 g (0.58 mol) of DEPI was added dropwise from the dropping funnel at 35°C. The resulting reaction mixture was stirred at 35°C for 2 hours and then at 60°C for 4 hours. After cooling and filtration, the sample was extracted from the reaction mixture using a... 31 P-NMR determined the composition of the phosphorus-containing component to be: 90.3 mol% DEHMP, 0.0 mol% DEPI, and 9.7 mol% unknown byproducts.

[0065] This shows that Comparative Example 1 (using potassium carbonate according to the synthesis method from CN 103073747 A1) retained a large amount of unconverted DEPI. Additionally, side reactions reduced the DEHMP yield to 82%. Comparative Example 2, using less potassium carbonate, produced slightly fewer byproducts but also provided a lower DEPI conversion. Comparative Examples 3 through 5 show that using inorganic bases lithium carbonate, calcium oxide, and calcium hydroxide did not produce any improvement. Comparative Example 6 shows that, without the addition of a basic catalyst, the desired reaction progressed very slowly and only provided a low yield of the target product. Comparative Examples 7 and 8 demonstrate that the preparation method disclosed in CN 105 541 910 A, using more than 3 mol% potassium carbonate or sodium carbonate, resulted in lower yields and an increased proportion of byproducts.

[0066] Conversely, in Examples 1 to 7 of the present invention, only a very small proportion of converted DEPI or even no converted DEPI was present under the same reaction conditions as in Comparative Example 3, and the DEHMP yield was 90% or higher.

Claims

1. A method for preparing diethyl hydroxymethylphosphonate by reacting diethyl phosphite with paraformaldehyde, characterized in that, The reaction is carried out in the presence of sodium carbonate in an amount of 1 to 3 mol% relative to the amount of DEPI used.

2. The method according to claim 1, characterized in that, The reaction was carried out in the presence of sodium carbonate in an amount of 2 to 3 mol% relative to the amount of DEPI used.

3. The method according to one or more of claims 1 and 2, characterized in that, The method is carried out in the presence of an organic solvent, preferably an organic solvent with a water content of less than 5% by weight, more preferably less than 1% by weight, and particularly preferably less than 0.2% by weight.

4. The method according to claim 3, characterized in that, The organic solvent is selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, diethyl hydroxymethylphosphonate, toluene, xylene, cyclohexane, n-heptane, dichloromethane, chlorobutane, diethyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, triethyl phosphate, and mixtures thereof.

5. The method according to one or more of claims 3 and 4, characterized in that, Ethanol is used as the organic solvent.

6. The method according to one or more of claims 1 to 5, characterized in that, The sodium carbonate in question is anhydrous sodium carbonate (CAS No. 497-19-8).

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 of 5 to 75°C, preferably 15 to 65°C, and particularly preferably 25 to 55°C.

8. The method according to one or more of claims 1 to 7, characterized in that, Paraformaldehyde and optionally an organic solvent are pre-placed in a reactor and then diethyl phosphite is metered into it.

9. The method according to one or more of claims 1 to 7, characterized in that, Paraformaldehyde, sodium carbonate, and optionally an organic solvent are pre-placed in a reactor and then metered into it.

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

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

12. The method according to one or more of claims 1 to 11, characterized in that, The reaction proceeds until... 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, The diethyl hydroxymethylphosphonate was not purified by adding water and extracting it from the aqueous phase with an organic solvent after the reaction.