Preparation process of methylene dicarboxylic acid ester

Abstract

This invention relates to a process for preparing compounds having formula (I): R 1 ‑C(=O)‑O‑CH2‑O‑C(=O)‑R 2 (I), where R 1 and R 2 Each of the terms represents an alkyl, cycloalkyl, or aryl group independently, wherein the alkyl, cycloalkyl, or aryl group is optionally substituted; the process includes step i) reacting the following substances: compound A selected from: trioxane, polyoxymethylene without a hydroxyl terminal group; compound (II): R 1 -C(=O)-O-C(=O)-R 2 (II); and perfluorosulfonic acid; wherein step i) is carried out at a temperature T1 of at least 50°C, wherein the molar ratio of compound (II) to compound A is 1:1 to 1.2:1.

Description

Technical Field

[0001] This invention relates to the preparation process and uses of methylene dicarboxylic acid esters. Background Technology

[0002] Methylene dicarboxylic acid esters are a class of compounds that are diesters of methyl glycol. These compounds have historically been used for fungal and bacterial control in crop and animal feedstocks, as well as for acylating agents in plasticizing and stabilizing polyoxymethylene. They are also used as starting materials for the preparation of cyanoacrylates.

[0003] Some processes are known and consist of reacting solid paraformaldehyde with carboxylic anhydrides and a catalyst. However, these processes have several drawbacks, such as achieving high viscosity (which means stirring problems) and exothermic reactions (which mean difficulty in controlling the reaction temperature). Furthermore, high catalyst loading is typically required to complete the reaction. Finally, the resulting product needs further purification via a neutralization step and further complex fractionation to obtain a pure product. Therefore, on an industrial scale, these processes are complex, time-consuming, energy-intensive, and generate waste due to byproduct formation and the use of alkaline neutralizing agents in the work-up step.

[0004] Therefore, new processes are needed to overcome at least partially one or more of the aforementioned drawbacks.

[0005] More specifically, there is a need for a process for preparing methylene dicarboxylic acid esters that exhibits high conversion, high yield, and high purity of all starting materials.

[0006] There is a need for a process for preparing methylene dicarboxylic acid esters that can be carried out continuously, with low catalyst loading, controlled exothermicity, and is rapid. Summary of the Invention

[0007] This invention relates to a process for preparing compounds having formula (I):

[0008] R 1 -C(=O)-O-CH2-OC(=O)-R 2 (I)

[0009] Where R 1 and R 2 Each of the terms represents an alkyl, cycloalkyl, or aryl group independently, wherein the alkyl, cycloalkyl, or aryl group may optionally be substituted.

[0010] The process includes step i) reacting the following substances:

[0011] Compound A is selected from the following: trioxane and polyoxymethylene without hydroxyl end groups;

[0012] Compound of formula (II):

[0013] R 1 -C(=O)-OC(=O)-R 2 (II)

[0014] and

[0015] Perfluorosulfonic acid;

[0016] Step i) is performed at a temperature T1 of at least 50°C.

[0017] The molar ratio of compound (II) to compound A is 1:1 to 1.2:1.

[0018] Preferably, the molar ratio of compound (II) to compound A is 1:1 to 1.1:1, and even more preferably 1:1 to 1.05:1.

[0019] Compound of formula (I)

[0020] The compounds of formula (I) are preferably those of the following, wherein:

[0021] - R 1 Represents optionally substituted alkyl groups; and

[0022] - R 2 Represents an alkyl group that is optionally substituted.

[0023] The preferred compounds of formula (I) are those that are:

[0024] - R 1 Represents an alkyl group containing 1 to 10 carbon atoms; and

[0025] - R 2 Represents an alkyl group containing 1 to 10 carbon atoms.

[0026] R 1 and R 2 The representative alkyl groups can independently include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 2-methylbutyl, hexyl, and isohexyl.

[0027] Preferably, in the compound of formula (I), R 1 and R 2 same.

[0028] More preferably, the compound of formula (I) is:

[0029] CH3-C(=O)-O-CH2-OC(=O)-CH3

[0030] Compound of formula (II)

[0031] Compounds of formula (II) are preferably those of the following, wherein:

[0032] - R 1 Represents optionally substituted alkyl groups; and

[0033] - R 2 Represents an alkyl group that is optionally substituted.

[0034] The preferred compounds of formula (II) are those that are:

[0035] - R 1 Represents an alkyl group containing 1 to 10 carbon atoms; and

[0036] - R 2 Represents an alkyl group containing 1 to 10 carbon atoms.

[0037] R 1 and R 2 The representative alkyl groups can independently include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 2-methylbutyl, hexyl, and isohexyl.

[0038] Preferably, in the compound of formula (II), R 1 and R 2 same.

[0039] More preferably, the compound of formula (II) is:

[0040] CH3-C(=O)-OC(=O)-CH3

[0041] Compounds of formula (II) are typically carboxylic anhydrides and can be prepared from carboxylic acids by methods known in the art. Compounds of formula (II) are also commercially available from Sigma Aldrich.

[0042] Compound A

[0043] Compound A is selected from: trioxane and polyoxymethylene without hydroxyl end groups.

[0044] Preferably, compound A is trioxane, and more preferably 1,3,5-trioxane.

[0045] Trioxane is available commercially from Sigma Aldrich, for example.

[0046] Polyoxymethylene (POM) without hydroxyl end groups is, for example, commercially available POM (Delrin) from DuPont.

[0047] Perfluorosulfonic acid

[0048] Perfluorosulfonic acids typically have the following formula: C n F 2n+1 SO3H, where n is an integer.

[0049] Preferably, the perfluorosulfonic acid is selected from: trifluoromethanesulfonic acid, perfluoroethanesulfonic acid, perfluoropropanesulfonic acid, perfluorobutanesulfonic acid, perfluoropentanesulfonic acid, perfluorohexanesulfonic acid, perfluoroheptanesulfonic acid, perfluorooctanesulfonic acid, perfluorononanesulfonic acid, and perfluorodecanesulfonic acid.

[0050] More preferably, perfluorosulfonic acid is trifluoromethanesulfonic acid.

[0051] Perfluorosulfonic acid is preferably used at a mol% of 0.01 mol% to 0.1 mol%, more preferably 0.01 to 0.05 mol%, relative to 100 mol% of the compound of formula (II).

[0052] Perfluorosulfonic acid is typically a catalyst that does not react with other compounds and is recovered at the end of the reaction.

[0053] step

[0054] Step i) can be carried out solvent-free or in the presence of a solvent. If present, the solvent may be a polar solvent, such as xylene, dibutyl ether, ethylene glycol diacetate, or mixtures thereof.

[0055] Preferably, step i) is carried out without solvent.

[0056] Step i) can be carried out in an inert atmosphere, such as in the presence of nitrogen, argon or helium.

[0057] Preferably, step i) is carried out in a reactor.

[0058] Step i) can last from 1 hour to 24 hours, preferably from 1 hour to 10 hours, and even more preferably from 1 hour to 4 hours.

[0059] Step i) is preferably carried out at a temperature T1 greater than or equal to 80°C, and even more preferably at a temperature T1 between 100°C and 200°C.

[0060] Step i) can be carried out in the presence of the compound of formula (IV):

[0061] R 1 -C(=O)-OH (IV)

[0062] Where R 1It is an alkyl, cycloalkyl, or aryl group, wherein the alkyl, cycloalkyl, or aryl group may optionally be substituted.

[0063] Compound of formula (IV) is preferably wherein R 1 Those representing optionally substituted alkyl groups, more preferably wherein R 1 Those that represent alkyl groups containing 1 to 10 carbon atoms.

[0064] Preferably, R in compound (IV) 1 R in compounds of formulas (I) and (II) 1 same.

[0065] More preferably, the compound of formula (IV) is:

[0066] CH3-C(=O)-OH

[0067] Preferably, the content of compound (IV) is 2% to 10% by weight, based on the total mass of the reaction medium. More preferably, it is 4% to 6% by weight, based on the total mass of the reaction medium.

[0068] Step i) is preferably carried out in the absence of cyanoacetic acid ester compounds.

[0069] Step i) is preferably carried out in the absence of carbon monoxide.

[0070] Step i) is preferably performed in the absence of Group VIII noble transition metal compounds.

[0071] Step i) is preferably carried out in the absence of any compounds other than compound A, compound (II), perfluorosulfonic acid and optionally compound (IV).

[0072] This process can be carried out in a single reactor or in a reactor cascade. The reactor can be a tubular reactor.

[0073] This process can be carried out continuously or in batches.

[0074] The process of the present invention preferably includes step i' (before or simultaneously with step i), contacting the compound of formula (II), compound A, and perfluorosulfonic acid.

[0075] This step i') may include:

[0076] - Contact the perfluorosulfonic acid with a mixture containing the compound of formula (II) and compound A (the contacting step may be, for example, adding the perfluorosulfonic acid to the mixture, or adding the mixture to the perfluorosulfonic acid);

[0077] or

[0078] - Contact compound A with a mixture containing compound (II) and perfluorosulfonic acid (the contacting step may be, for example, adding compound A to the mixture, or adding the mixture to compound A);

[0079] or

[0080] - Contact compound A, compound (II) and perfluorosulfonic acid simultaneously (e.g., in the case where each compound is fed into the reactor separately).

[0081] Contact step i') can be performed at a temperature T2 that is lower than or equal to T1. If the temperature T2 is different from T1, it can be from 20°C to 49°C, preferably from 20°C to 30°C.

[0082] If temperature T2 is different from T1, the process preferably includes a heating step from T2 to T1 (ii').

[0083] Step i) preferably results in a composition containing compound (I).

[0084] Advantageously, the process allows at least 90% of compound A to be converted into compound (I). Even more preferably, the process allows at least 96% of compound A to be converted into compound (I).

[0085] Advantageously, the process allows at least 80% of compound A to be converted into compound (I) within 1 hour.

[0086] The process may include a subsequent step ii) after step i) to collect the compound of formula (I).

[0087] Step ii) preferably includes contacting the composition obtained after step i) with the adsorbent material.

[0088] The adsorbent material can be a solid material with basic, acidic, or neutral properties that is insoluble in the reaction mixture.

[0089] Preferably, the adsorbent material is clay, zeolite, alumina, silica gel, activated carbon, magnesium silicate (e.g., magnesol), calcium carbonate, calcium stearate, or alkaline ion exchange resin.

[0090] More preferably, the adsorbent material is clay (preferably bentonite) or inorganic silicate.

[0091] Step ii) is preferably carried out at a temperature of 20°C to 30°C, and even more preferably at 23°C.

[0092] Step ii) advantageously allows for the separation of perfluorosulfonic acid from the compound of formula (I).

[0093] The compound of formula (I) obtained after step ii) advantageously has high purity, preferably at least 90%, more preferably at least 92%.

[0094] Compound (I) preferably contains less than 5% by weight, more preferably less than 2% by weight, of impurities selected from compounds (II), (III), and mixtures thereof:

[0095] R 1 -C(=O)-O-CH2-O-CH2-OC(=O-R 2 (III)

[0096] Where R 1 and R 2 As defined above.

[0097] The process may include an intermediate step between step i) and step ii), which involves subjecting the medium obtained after step i) to moisture. This can be accomplished by mixing at a temperature between 20°C and 80°C.

[0098] Advantageously, the process does not include a purification step after step ii). More preferably, the process does not include a distillation step after step ii).

[0099] The process is also preferably free of a neutralization step after step i) and / or step ii).

[0100] The process according to the invention exhibits at least one of the following advantages:

[0101] - To result in a compound of formula (I) with reduced impurity levels in an atom-economic way;

[0102] - High conversion rates for all starting materials;

[0103] - High yield;

[0104] - The high purity of the compound of formula (I) eliminates the need for additional distillation steps, thus reducing its carbon footprint compared to other processes involving fractionation;

[0105] - Almost no catalyst is consumed;

[0106] - Process energy saving;

[0107] - The process is safe and there are no exothermic issues;

[0108] - The process is quick.

[0109] The present invention also relates to compounds of formula (I) obtained by the process disclosed herein.

[0110] This invention relates to compositions comprising compounds of formula (I) obtained by the process disclosed herein.

[0111] The present invention also relates to the use of compounds of formula (I) obtained by the process disclosed herein for the preparation of cyanoacrylates.

[0112] The ranges disclosed in this specification include both their lower and upper limits. For example, the statements "range from x to y (within the range of x to y, x to y)" or "between x and y" include the extreme values ​​of x and y.

[0113] Experimental Section

[0114] Example 1 Preparation of methylene diacetate (sulfuric acid, comparative)

[0115] In a 250 mL flask, 30 g of trioxane (from Sigma Aldrich) was dissolved in 102 g of Ac₂O (acetic anhydride from Sigma Aldrich). The flask was not immersed in any bath to assess the exothermic nature of the process. During the dissolution process, the solution temperature was reduced from 23 °C to 8 °C. The cold mixture was then immersed in an oil bath, heated to 23 °C, and maintained at 23 °C for 1 hour. Analysis of the solution showed no reaction.

[0116] Following this, the oil bath was removed, and 0.49 g of sulfuric acid (0.5 mol%, from Scharlau), dissolved in 6.8 g of acetic acid (corresponding to 5% of the final mass, from ThermoFisher), was added dropwise to the stirred solution. Upon addition of the catalyst, the exothermic reaction had already begun, and the temperature of the mixture had risen to 82 °C.

[0117] After the exothermic reaction was complete, the mixture was immersed again in an oil bath and heated at 140°C for 4 hours. The mixture was analyzed by NMR after heating for 0, 1, 2, and 4 hours.

[0118] Example 2 is a repeat, but uses 1 mol% sulfuric acid (comparison).

[0119] Example 3 is a repeat, but uses 0.02 mol% (~200 ppm) of trifluoromethanesulfonic acid (in this invention).

[0120] Figure 1 The content of methylene diacetate (wt%) was disclosed relative to time (x-axis) in hours.

[0121] according to Figure 1Example 1 (comparative), catalyzed by 0.5 mol% sulfuric acid (SA), resulted in approximately 50 wt% methylene diacetate after 1 hour and less than 80 wt% methylene diacetate after 4 hours. Conversely, Example 3 (200 ppm trifluoromethanesulfonic acid: TFA) advantageously resulted in a high wt% methylene diacetate (greater than 80 wt%) after only 1 hour, using a much lower catalyst amount (200 ppm by weight). For Example 3, the reaction lasted from 1 to 2 hours. Therefore, the reaction of the examples catalyzed by trifluoromethanesulfonic acid was advantageously faster with the use of a smaller amount of catalyst.

[0122] Figure 2 The weight percentage (wt%) of dioxymethylene diacetate (DOD) over time (in hours) is disclosed.

[0123] Figure 2 The consumption of residual DOD in Example 2 (with 1 mol% SA - comparative) and Example 3 (with ~200 ppm TFA - of the present invention) is shown.

[0124] In the reaction catalyzed by 1 mol% SA (Example 2 - Comparative), the residual DOD level decreased to 2.5% by weight after heating for 4 hours, and in the reaction catalyzed by 200 ppm TFA (Example 3 - Invention), it had already decreased to below this value in just 1 to 2 hours.

[0125] Example 4 Example 3: Post-treatment via adsorption filtration (work-up)

[0126] The reaction mixture containing the prepared methylene diacetate, obtained in Example 3 by catalysis with 200 ppm TFA, was filtered through an adsorbent without any additional workup.

[0127] Using a small Chemrus disposable filter funnel (polypropylene body, 10 μm pore size) as a carrier, the mixture from Example 3 was slowly filtered through a preformed plug of 2.8 g (2 wt% relative to the total mass of the reaction mixture). The filtration took a total of 6 hours under a vacuum of 200 mbar. The filtrate was light brown, but much clearer than the coarse mixture containing some black particles.

[0128] The NMR analysis of the filtrate corresponds to the NMR spectrum of the reaction mixture before filtration.

[0129] Example 5 Example 3: Post-treatment via adsorption filtration

[0130] The reaction mixture containing the prepared methylene diacetate, obtained in Example 3 by catalysis with 200 ppm TFA, was filtered through an adsorbent without any additional post-treatment.

[0131] Using a small Chemrus disposable filter funnel (polypropylene body, 10 micrometer pore size) as a carrier, the mixture from Example 3 was slowly filtered through a pre-made stopper containing 2.8 g (2 wt% relative to the total mass of the reaction mixture). Filtration took a total of 30 minutes under a vacuum of 200 mbar. The filtrate was light brown, but much clearer than the coarse mixture containing some black particles.

[0132] The NMR analysis of the filtrate corresponds to the NMR spectrum of the reaction mixture before filtration.

[0133] Example 6 Preparation of 2-methoxyethyl cyanoacrylate (MECA)

[0134] The synthesis of 2-methoxyethyl cyanoacrylate (MECA) was carried out according to the method disclosed in EP2927209 (particularly Example 1), using the corresponding methylene diacetate, on a 10 mmol scale, in the presence of a free radical stabilizer known to those skilled in the art, from 2-methoxyethyl cyanoacrylate.

[0135] The components of this reaction are as follows:

[0136]

[0137] The reaction was carried out at 125 °C using three different methylene diacetate samples (6a, 6b, 6c), and the crude reaction mixture was analyzed by NMR after 90 minutes of reaction.

[0138] In Example 6a: Methylene diacetate provided by CMC was purified by fractional distillation (comparative).

[0139] In Example 6b: the methylene diacetate obtained in Example 4 (after adsorption filtration, according to the present invention)

[0140] In Example 6c: the methylene diacetate obtained in Example 5 (after adsorption filtration, according to the present invention)

[0141]

[0142] As can be seen from the table, the conversion rate of 2-methoxyethyl cyanoacetate in Examples 6b and 6c (of the present invention) is advantageously higher than that in Example 6a (comparative): in fact, the content of unreacted 2-methoxyethyl cyanoacetate is lower, at 1.6% (6b) and 2.1% (6c), compared to 3.5% (6a).

[0143] Furthermore, compared to Example 6a (83%), the selectivity in Examples 6b and 6c (of the present invention) (86%) is advantageously higher: the reactivity of the methylene diacetate sample purified solely by contact with the adsorbent material is superior to that of methylene diacetate obtained and purified by conventional methods (fractionation).

[0144] Example 7 Continuous preparation of methylene diacetate in a reactor cascade

[0145] In a 500 mL flask, 60 g of trioxane was dissolved in 204 g of Ac₂O without immersion in any bath to assess the exothermic nature of the process. During the dissolution process, the temperature of the solution dropped from room temperature (rt) to ~8 °C. Afterward, a solution of 0.6 g of 10% TFA (trifluoromethanesulfonic acid) in acetic acid (diluted with an additional 13 g of pure acetic acid) was added dropwise to the stirred solution. Upon addition of the catalyst, the exothermic reaction had already begun, and the temperature of the mixture rose to 91 °C.

[0146] After the first step of exothermic reaction is completed, the mixture (with a density of 1.12 g / mL) is immersed in T... 浴 Two reactors are cascaded in an oil bath at 150°C to maintain the internal temperature at 140°C.

[0147] The setup representing two cascaded reactors consists of two flasks and three peristaltic pumps with PTFE tubing. Peristaltic pump 1 is used to add the mixture from the feed container to flask 1 (representing "reactor 1") after the first step. Peristaltic pump 2 is used to transfer the liquid from flask 1 to flask 2 (representing "reactor 2"), and peristaltic pump 3 is used to transfer the liquid from flask 2 to the receiver container at a rate of approximately 1.0 mL / min. This rate ensures a residence time of approximately 2 hours for the mixture in the reactor.

[0148] - At the beginning (t=0-2 hours), only pump 1 is turned on to fill flask 1.

[0149] Then (t=2-4 hours), turn on pump 2 to start transferring liquid from flask 1 to flask 2, keeping the liquid level in flask 1 constant until flask 2 is also full.

[0150] - After this (t=4-6 hours), turn on pump 3 to transfer the liquid from flask 2 to the receiver cylinder. Once no liquid remains in the feed cylinder, turn off pump 1. During this period, the liquid level in flask 2 remains constant.

[0151] - Finally (t=6-8 hours), no liquid remains in flask 1 (pump 2 is also turned off), and the process continues until flask 2 is empty.

[0152] The feed mixture contains 32% methylene diacetate, and at a residence time of 2 hours, the steady state in flask 1 reaches ~80% methylene diacetate, and at a steady state in flask 2 reaches ~90% methylene diacetate, which is equal to the methylene diacetate content at the end of the batch reaction.

Claims

1. Process for preparing compounds having formula (I): R 1 -C(=O)-O-CH2-O-C(=O)-R 2 (I) Where R 1 and R 2 Each of the terms represents an alkyl, cycloalkyl, or aryl group independently, wherein the alkyl, cycloalkyl, or aryl group may optionally be substituted. The process includes step i) of causing the following reaction: Compound A is selected from the following: trioxane and polyoxymethylene without hydroxyl end groups; Compound of formula (II): R 1 -C(=O)-OC(=O)-R 2 (II) and Perfluorosulfonic acid; Step i) is performed at a temperature T1 of at least 50°C. The molar ratio of compound (II) to compound A is 1:1 to 1.2:

1.

2. The process according to claim 1, wherein the molar ratio of compound (II) to compound A is 1:1 to 1.1:

1.

3. The process according to any one of claims 1 or 2, wherein the molar ratio of compound (II) to compound A is 1:1 to 1.05:

1.

4. The process according to any one of claims 1-3, wherein step i) is carried out at a temperature T1 greater than or equal to 80°C, preferably at a temperature T1 between 100°C and 200°C.

5. The process according to any one of claims 1-4, wherein step i) is carried out in the presence of the compound of formula (IV): R 1 -C(=O)-OH (IV) Where R 1 It is an alkyl, cycloalkyl, or aryl group, wherein the alkyl, cycloalkyl, or aryl group may optionally be substituted.

6. The process according to any one of claims 1-5, wherein the content of the compound of formula (IV) is 2% to 10% by weight based on the total mass of the reaction medium, preferably 4% to 6% by weight based on the total mass of the reaction medium.

7. The process according to any one of claims 1-6, wherein the compound of formula (I) is selected from those of: - R 1 Represents an alkyl group containing 1 to 10 carbon atoms; and - R 2 Represents an alkyl group containing 1 to 10 carbon atoms.

8. The process according to any one of claims 1-7, wherein the compound of formula (I) is: CH3-C(=O)-O-CH2-OC(=O)-CH3.

9. The process according to any one of claims 1-8, wherein compound A is trioxane.

10. The process according to any one of claims 1-9, wherein the perfluorosulfonic acid is selected from: trifluoromethanesulfonic acid, perfluoropropanesulfonic acid, perfluoroethanesulfonic acid, perfluorobutanesulfonic acid, perfluoropentanesulfonic acid, perfluorohexanesulfonic acid, perfluoroheptanesulfonic acid, perfluorooctanesulfonic acid, perfluorononanesulfonic acid, and perfluorodecanesulfonic acid.

11. The process according to any one of claims 1-10, wherein the perfluorosulfonic acid is trifluoromethanesulfonic acid.

12. The process according to any one of claims 1-11, wherein, Perfluorosulfonic acid is used in 0.01 mol% to 0.05 mol% relative to the compound of formula (II).

13. The process according to any one of claims 1-12, wherein the process allows at least 90% of compound A to be converted into compound (I).

14. The process according to any one of claims 1-13, wherein it further comprises a subsequent step ii) of collecting the compound of formula (I) after step i).

15. The process according to any one of claims 1-14, wherein step ii) comprises contacting the composition obtained after step i) with an adsorbent material, wherein the adsorbent material is preferably selected from clay, zeolite, alumina, silica gel, activated carbon, magnesium silicate, calcium carbonate, calcium stearate, and basic ion exchange resin, and more preferably, the adsorbent material is clay or inorganic silicate.

16. The process according to any one of claims 1-15, wherein the compound of formula (I) obtained after the collection step has a purity of at least 90%, preferably at least 92%.

17. The process according to any one of claims 1-16, wherein the process does not include a purification step after step ii).

18. The compound of formula (I) obtained by the process according to any one of claims 1-17.

19. Use of the compound of formula (I) according to claim 18 for the preparation of cyanoacrylates.

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