One-step synthesis of 2-fluoroalkyl acrylates

Abstract

A method for producing alkyl halogenated acrylates is provided, wherein the method involves reacting a dialkyl halomalonic acid ester or a diaryl halomalonic acid ester with an aldehyde, preferably formalin or paraformaldehyde, and a base catalyst to produce an intermediate, and heating the intermediate without separating the intermediate to produce the alkyl halomalonic acid ester. This synthesis can be a one-pot process, meaning that it reacts in the same vessel and / or reaction mixture without the need to separate the intermediate, and thus improves the yield. In particular, a method for producing alkyl 2-fluoroacrylates is provided.

Description

Technical Field

[0001] This invention relates to a one-step method for synthesizing 2-haloacrylates. This method eliminates the need for intermediate separation and improves yield compared to methods used in the art. Background Technology

[0002] 2-Haloalkyl acrylates (especially 2-fluoroalkyl acrylates) can be used as monomers in the preparation of a variety of polymers. These poly(2-haloalkyl acrylates) can be used in films, in plastics, and in pharmaceuticals.

[0003] Various methods for preparing alkyl 2-haloacrylates have been disclosed in the literature. However, these methods have many drawbacks, including low product yields and / or the need to separate intermediates, as well as the use of highly toxic reagents.

[0004] US 3,262,968 (Example 1) describes a method for preparing methyl α-fluoroacrylate, which involves mixing dimethyl oxalate with methyl fluoroacetate in the presence of sodium methoxide. The reported conversion of methyl fluoroacetate is 89%. However, this method uses excessive solvent (greater than 170 parts tetrahydrofuran and 650 parts dichloromethane), and the product mixture contains significant amounts of residual methyl fluoroacetate (classified as “extremely hazardous” by the World Health Organization).

[0005] Gassen et al., *Journal of Fluorine Chemistry*, 55, (1991) 149-162, describe a method for preparing 2-fluoroacrylates involving the hydrolysis of hydroxymethyl-fluoromalonate, followed by decarboxylation and re-esterification. CA1280118C describes a method for synthesizing fluoroacrylates (e.g., methyl α-fluoroacrylate), involving the hydroxymethylation of dialkyl malonate with formaldehyde, separation of intermediates, acid hydrolysis, and further purification. The reported yield is 58%. WO 2015 / 193392 describes a method for preparing 2-haloacrylates involving the hydroxymethylation of dialkyl malonate with formaldehyde, separation of intermediates, followed by nucleophilic halogenation and decarboxylation. The reported yield is less than 70%. The additional processing steps and low yields make these methods undesirable for many applications.

[0006] This specification provides a method for synthesizing 2-haloacrylate alkyl esters, which occurs in the same container and / or reaction mixture, eliminates the need for intermediate separation, eliminates the need for highly toxic reagents, reduces synthetic steps, and improves yield compared to methods used in the art. Summary of the Invention

[0007] This article discloses a method for preparing haloacrylate compounds, the method comprising preparing a malonate compound corresponding to the structure of Formula 1.

[0008] (1)

[0009] The reaction mixture is contacted with an aldehyde to form a reaction mixture, wherein each R1 group is independently alkyl or aryl, and X is fluorine, chlorine, bromine, or iodine; and the reaction mixture is heated in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2.

[0010] (2)

[0011] R2 is hydrogen, alkyl, or aryl, and the total yield of compounds corresponding to the structure of Formula 2 is at least 75% based on the amount of compounds corresponding to the structure of Formula 1.

[0012] This article also discloses a method for preparing haloacrylate compounds, the method comprising preparing compounds corresponding to the structure of Formula 1.

[0013] (1)

[0014] The reaction mixture is contacted with an aldehyde to form a reaction mixture, wherein each R1 group is independently alkyl or aryl, and X is fluorine, chlorine, bromine, or iodine; and the reaction mixture is heated in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2.

[0015] (2)

[0016] R2 is hydrogen, alkyl, or aryl, and the conversion of the compound corresponding to the structure of Formula 1 to the compound corresponding to the structure of Formula 2 occurs in the same reaction mixture.

[0017] This article also discloses a method for preparing fluoroacrylate compounds, the method comprising preparing compounds corresponding to the structure of Formula 3.

[0018] (3)

[0019] The reaction mixture is contacted with formaldehyde, preferably oligooxymethylene or formalin to form a reaction mixture, wherein each R1 group is independently alkyl or aryl; and the reaction mixture is heated in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 4.

[0020] (4)

[0021] The total yield of compounds corresponding to the structure of Formula 4 is at least 75%, based on the amount of compounds corresponding to the structure of Formula 3.

[0022] This article also discloses a method for preparing fluoroacrylate compounds, the method comprising preparing compounds corresponding to the structure of Formula 3.

[0023] (3)

[0024] The reaction mixture is contacted with formaldehyde, preferably oligooxymethylene or formalin to form a reaction mixture, wherein each R1 group is independently alkyl or aryl; and the reaction mixture is heated in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 4.

[0025] (4)

[0026] The conversion of the compound corresponding to the structure of Formula 3 to the compound corresponding to the structure of Formula 4 occurs in the same reaction mixture.

[0027] Additionally, this disclosure relates to a method for preparing patiromer calcium sorbitol, the method comprising preparing a fluoroacrylate of formula 2A by the method described herein; forming a polymerization reaction mixture comprising divinylbenzene, 1,7-octadiene, and a fluoroacrylate of formula 2A to form a crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; and deprotecting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer. Crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form a crosslinked (2-fluorocalcium acrylate)-divinylbenzene-1,7-octadiene polymer; swelling the crosslinked (2-fluorocalcium acrylate)-divinylbenzene-1,7-octadiene polymer and contacting it with sorbitol to form petiromer sorbitol calcium (i.e., a crosslinked (2-fluorocalcium acrylate)-divinylbenzene-1,7-octadiene polymer loaded with sorbitol).

[0028] Other purposes and features are partly obvious and partly will be noted below. Detailed Implementation

[0029] This article describes a method for preparing alkyl halogenated acrylates or aryl halogenated acrylates, wherein a dialkyl halogenated malonate or a diaryl halogenated malonate is contacted with an aldehyde, preferably formalin or paraformaldehyde, to form a reaction mixture, and the reaction mixture is typically heated in the presence of a base to form the alkyl halogenated acrylate or the aryl halogenated acrylate.

[0030] For the methods described herein, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or the conversion of a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture. This method does not require the separation of intermediates. Therefore, for batch methods, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or the conversion of a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture, typically in the same vessel. For continuous methods, the conversion of a compound corresponding to the structure of Formula 1 to a compound corresponding to the structure of Formula 2, or the conversion of a compound corresponding to the structure of Formula 3 to a compound corresponding to the structure of Formula 4, occurs in the same reaction mixture.

[0031] The method described herein is more efficient than existing methods in terms of reagent use and manufacturing steps because the synthesis can be carried out in a single reaction vessel without the need to transfer or separate intermediates. Furthermore, it improves product yield compared to existing methods for preparing alkyl 2-haloacrylates.

[0032] The production of methyl 2-fluoroacrylate (MFA) from dimethyl fluoromalonate (DMFM) can be accomplished in high yields using a simplified one-pot batch process. Formaldehyde sources (such as paraformaldehyde and formalin) can be used as reactants, with an excess of 10 mol% being sufficient.

[0033] This method typically uses solvents. Polar aprotic solvents are generally used, and high-boiling-point polar aprotic solvents are commonly employed. Typical solvents include dimethyl sulfoxide, N-methylpyrrolidone, and sulfolane; more typically, sulfolane is used.

[0034] The concentration of DMFM can range from 10 to 60 wt%, 20 to 50 wt%, and 30 to 40 wt%. Typically, the concentration of DMFM is in the range of 35 to 40 wt%; more typically, the concentration of DMFM is about 37 wt%.

[0035] In this method, a base is typically used as a catalyst. Organic bases, such as pyridine, pyrrolidine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene and (1,4-diazabicyclo[2.2.2]octane), can promote the reaction. Inorganic bases, such as alumina, calcium oxide and potassium carbonate, can also promote the reaction. Typically, potassium carbonate and cesium carbonate are used, with cesium carbonate yielding a higher yield.

[0036] The initial process temperature can range from 10 to 120°C. Adding the aldehyde reagent to the reaction mixture produces a rapid exothermic reaction. This exothermic reaction is considered a condensation reaction that produces an intermediate. Therefore, the temperature used to add formaldehyde is controlled below 30°C. After the exothermic reaction, the temperature of the reaction mixture is typically increased, and the reaction proceeds to form the desired product. This is considered a decarboxylation reaction.

[0037] The temperature for reactive distillation (e.g., decarboxylation and distillation) can be in the range of 60 to 150°C, 70 to 140°C, 80 to 135°C, 90 to 130°C, or 100 to 140°C; preferably, a temperature of about 110°C to 130°C or about 120°C is used. Lower temperatures can be used, but this may slow down the reaction and produce MFA in low yields.

[0038] The pressure for reactive distillation can be 50 to 1000 mbar, 70 to 750 mbar, 90 to 500 mbar, or 100 to 300 mbar; typically, the pressure is about 200 mbar. At lower pressures, more distillate can be collected at a faster rate; however, more solvent can also be collected.

[0039] The overall yield relative to the amount of the compound corresponding to Formula 1 (or the compound corresponding to Formula 3) can be 75% or higher, 80% or higher, 85% or higher, 90% or higher, 95% or higher, or 97% or higher. The overall yield relative to the amount of the compound corresponding to Formula 1 (or the compound corresponding to Formula 3) can be as high as 75%, as high as 80%, as high as 85%, as high as 90%, as high as 95%, or as high as 97%. The overall yield relative to the amount of the compound corresponding to Formula 1 (or the compound corresponding to Formula 3) can range from 75% to 97%, 80% to 95%, 85% to 97%, or 85% to 90%. As described herein, a crude (unpurified) yield of up to 92.7% was achieved relative to the amount of the compound corresponding to Formula 1 (or the compound corresponding to Formula 3).

[0040] In addition, this article discloses a method for preparing haloacrylate compounds, the method comprising contacting a compound corresponding to the structure of Formula 1 with an aldehyde, preferably paraformaldehyde or formalin, to form a reaction mixture comprising the aldehyde and a compound corresponding to the structure of Formula 1.

[0041] (1)

[0042] Each R1 group is independently alkyl or aryl, and X is fluorine, chlorine, bromine, or iodine; and the reaction mixture is heated in the presence of a base to form a haloacrylate compound corresponding to the structure of Formula 2.

[0043] (2)

[0044] Wherein R2 is hydrogen, alkyl or aryl, and (i) the total yield of compounds corresponding to the structure of Formula 1 is at least 75% based on the amount of compounds corresponding to the structure of Formula 2, or (ii) the conversion of compounds corresponding to the structure of Formula 1 to compounds corresponding to the structure of Formula 2 occurs in the same reaction mixture.

[0045] Typically, in the methods described herein with respect to compounds of Formulas 1 and 2, the aldehyde is paraformaldehyde or formalin, and R2 is hydrogen.

[0046] More typically, in the methods described herein with respect to compounds of formulas 1 and 2, the aldehyde is paraformaldehyde or formalin, R2 is hydrogen, and X is fluorine.

[0047] This article discloses a method for preparing fluoroacrylate compounds, the method comprising contacting a compound corresponding to the structure of formula 1A with paraformaldehyde or formalin to form a reaction mixture of paraformaldehyde or formalin and the compound corresponding to the structure of formula 1A.

[0048] (1A)

[0049] Each R1 group is independently alkyl or aryl; and the reaction mixture is heated in the presence of a base to form a fluoroacrylate compound corresponding to the structure of formula 2A.

[0050] (2A)

[0051] The total yield of compounds corresponding to the structure of Formula 2A is at least 75%, based on the amount of compounds corresponding to the structure of Formula 1A.

[0052] This article also discloses a method for preparing fluoroacrylate compounds, the method comprising contacting a compound corresponding to the structure of formula 1A with paraformaldehyde or formalin to form a reaction mixture of the aldehyde and the compound corresponding to the structure of formula 1A.

[0053] (1A)

[0054] Each R1 group is independently an alkyl group; and the reaction mixture is heated in the presence of a base to form a fluoroacrylate compound corresponding to the structure of formula 2A.

[0055] (2A)

[0056] The conversion of the compound corresponding to the structure of Formula 1A to the compound corresponding to the structure of Formula 2A occurs in the same reaction mixture.

[0057] Typically, in methods for preparing haloacrylates of Formula 2 or fluoroacrylates of Formula 2A, the reaction mixture contains paraformaldehyde or formalin.

[0058] Typically, in the methods described herein for preparing compounds corresponding to the structure of Formula 2 or Formula 2A, the total yield of the compounds is at least 75%, 80%, 85%, or 90% based on the amount (moles or equivalents) of the compounds corresponding to the structure of Formula 1 or Formula 1A.

[0059] In the methods described herein for preparing compounds corresponding to the structures of Formula 1, Formula 1A, Formula 2 and Formula 2A, R1 can be a C1-C6 alkyl group. Typically, R1 is methyl, ethyl or propyl, and more typically, R1 is methyl.

[0060] The base used in this method may include organic nitrogen base compounds, alkaline earth metal hydroxides, alkali metal hydroxides, alkaline earth metal carbonates, alkali metal carbonates, alkaline earth metal bicarbonates, alkali metal bicarbonates, or combinations thereof.

[0061] Bases may include aluminum oxide, calcium oxide, barium oxide, triethylamine, pyridine, pyrrolidine, morpholine, dimethylpyridine, methylpyridine, trimethylamine, tripropylamine, tributylamine, dimethylethylamine, dimethylpropylamine, dimethylbutylamine, diethylmethylamine, diethylpropylamine, diethylbutylamine, N,N-diisopropylmethylamine, N,N-diisopropylethylamine, N-ethyldiisopropylamine, N,N-dimethylethylamine, N,N-diethylbutylamine, 1,2-dimethylpropylamine, N,N-diethylmethylamine, N,N-dimethylisopropylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, N,N-dimethylbutylamine, 1,8-diazabicyclo[5.4.0]undecane -7-ene, 1,4-diazabicyclo[2.2.2]octane, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, strontium bicarbonate, barium bicarbonate, or combinations thereof; preferably, the base comprises lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or combinations thereof; more preferably, the base comprises potassium carbonate, cesium carbonate, or combinations thereof. Typically, the base comprises cesium carbonate.

[0062] The reaction mixture can be heated to a temperature of at least about 110°C, about 110°C to about 170°C, about 110°C to about 160°C, about 110°C to about 150°C, about 110°C to about 140°C, about 110°C to about 130°C, about 115°C to about 170°C, about 115°C to about 160°C, about 115°C to about 150°C, about 115°C to about 140°C, about 115°C to about 130°C, or about 115°C to about 125°C.

[0063] The reaction mixture can be heated to reflux.

[0064] The reaction mixture may be heated for at least about 30 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 105 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 75 minutes, about 30 minutes to about 60 minutes, about 45 minutes to about 120 minutes, about 45 minutes to about 105 minutes, about 45 minutes to about 90 minutes, about 45 minutes to about 75 minutes, about 45 minutes to about 60 minutes, or about 50 minutes to about 70 minutes.

[0065] The methods disclosed herein may allow the reaction mixture to contain 1 equivalent of a compound corresponding to the structure of Formula 1 or Formula 1A and more than 1 equivalent of paraoxymethylene. Preferably, the reaction mixture contains about 1.1 to about 3, about 1.1 to about 2.5, about 1.1 to about 2, about 1.1 to about 1.7, about 1.1 to about 1.5, or about 1.1 to about 1.3 equivalents of paraoxymethylene.

[0066] Based on the amount (moles) of the compound corresponding to the structure of Formula 1 or Formula 1A, the reaction mixture may contain about 0.05 to about 0.5 molar equivalents of base, about 0.05 to about 0.4 molar equivalents of base, about 0.05 to about 0.3 molar equivalents of base, about 0.05 to about 0.2 molar equivalents of base, about 0.05 to about 0.15 molar equivalents of base, about 0.1 to about 0.5 molar equivalents of base, about 0.1 to about 0.4 molar equivalents of base, about 0.1 to about 0.3 molar equivalents of base, about 0.1 to about 0.2 molar equivalents of base, about 0.1 to about 0.15 molar equivalents of base, or about 0.1 molar equivalents of base.

[0067] The reaction mixture may further contain a solvent.

[0068] Solvents can include polar aprotic solvents.

[0069] The solvent may include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, ethylene glycol, polyethylene glycol, polypropylene glycol, ethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, quinoline, tetrahydroquinoline, N-methylpyrrolidone, dimethylimidazolium ketone, sulfolane, glycol dimethyl ether, diethylene glycol dimethyl ether, or combinations thereof. Typically, the solvent includes dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, or combinations thereof; more typically, the solvent is sulfolane.

[0070] The concentration of the compound corresponding to the structure of Formula 1 or Formula 1A in the reaction mixture may be from about 2 wt% to about 50 wt%, from about 5 wt% to about 50 wt%, from about 10 wt% to about 50 wt%, from about 15 wt% to about 50 wt%, from about 20 wt% to about 50 wt%, from about 25 wt% to about 50 wt%, from about 30 wt% to about 50 wt%, or from about 35 wt% to about 50 wt%. About 2% by weight to about 45% by weight, about 5% by weight to about 45% by weight, about 10% by weight to about 45% by weight, about 15% by weight to about 45% by weight, about 20% by weight to about 45% by weight, about 25% by weight to about 45% by weight, about 30% by weight to about 45% by weight, about 35% by weight to about 45% by weight, about 2% by weight to about 40% by weight, about 5% by weight to about 40% by weight, about 10% by weight to about 40% by weight, about 15% by weight to about 40% by weight, about 20% by weight to about 40% by weight, about 25% by weight to about 40% by weight, about 30% by weight to about 40% by weight, or about 35% by weight to about 40% by weight.

[0071] The pressure of the reaction mixture can be from about 50 mbar (5 kPa) to about 1000 mbar (100 kPa), from about 50 mbar (5 kPa) to about 800 mbar (80 kPa), from about 50 mbar (5 kPa) to about 600 mbar (60 kPa), from about 50 mbar (5 kPa) to about 400 mbar (40 kPa), from about 50 mbar (5 kPa) to about 300 mbar (30 kPa), from about 100 mbar (10 kPa) to about 1000 mbar (100 kPa), from about 100 mbar (10 kPa) to about 800 mbar (80 kPa), from about 100 mbar (10 kPa) to about 600 mbar (60 kPa), from about 100 mbar (10 kPa) to about 400 mbar (40 kPa), or from about 100 mbar (10 kPa) to about 300 mbar (30 kPa). kPa); preferably, about 100 mbar (10 kPa) to about 300 mbar (30 kPa). Typically, the pressure of the reaction mixture can be 200 mbar (20 kPa).

[0072] Compounds corresponding to the structure of Formula 2 can be prepared according to the following synthetic scheme, wherein R1, R2 and X are as defined above.

[0073] (2)

[0074] Dimethyl fluoromalonate is available from Oakwood Chemical Products, Inc., Estile, South Carolina. Diethyl fluoromalonate is available from Sigma-Aldrich, St. Louis, Missouri.

[0075] Additionally, this disclosure includes a method for preparing paltiromere calcium sorbitol, the method comprising preparing a fluoroacrylate of formula 2A by means of the methods described herein; forming a polymerization reaction mixture comprising divinylbenzene, 1,7-octadiene and a fluoroacrylate of formula 2A to form a crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; deprotecting the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; and swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting it with sorbitol to form paltiromere calcium sorbitol.

[0076] The polymerization reaction mixture comprises divinylbenzene, 1,7-octadiene, a fluoroacrylate of formula 2A, and a polymerization initiator.

[0077] The polymerization initiator contains lauroyl peroxide.

[0078] The method described herein includes deprotecting a crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer comprising hydrolyzing the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

[0079] The method includes hydrolyzing a crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer containing a crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a strong base.

[0080] A strong base is a water-based strong base.

[0081] Aqueous strong bases include sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, or combinations thereof; preferably, aqueous strong bases include sodium hydroxide.

[0082] When using a strong base of sodium hydroxide, the method includes transforming the formed (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer into a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

[0083] The method includes contacting a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer containing a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form a pulp.

[0084] The method further includes contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt to form a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer containing, and pulping the crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt.

[0085] Calcium salts include calcium chloride, calcium bromide, calcium iodide, or combinations thereof.

[0086] The method also includes swelling and crosslinking (2-fluoroacrylate calcium)-divinylbenzene-1,7-octadiene polymers by slurrying the polymer in a solution containing sorbitol.

[0087] The solution containing sorbitol is an aqueous solution of sorbitol.

[0088] Crosslinked cation exchange polymers (e.g., partiromere calcium sorbitol) can be synthesized by preparing an organic phase and an aqueous phase. The organic phase typically contains a polymerization initiator, a fluoroacrylate of formula 2A, 1,7-octadiene, and divinylbenzene. The aqueous phase typically contains a polymerization suspension stabilizer, a water-soluble salt, water, and optionally a buffer. The organic and aqueous phases are then combined and stirred under nitrogen. The mixture is typically heated to approximately 60°C to approximately 80°C for approximately 2.5 to approximately 3.5 hours, then raised to 95°C after initiation of polymerization, and then cooled to room temperature. After cooling, the aqueous phase is removed. Water is added to the mixture, the mixture is stirred, and the resulting solid is filtered. The solid is washed with water, alcohol, or an alcohol / water mixture.

[0089] As described above, polymerization suspension stabilizers, such as polyvinyl alcohol, are used to prevent particle agglomeration during polymerization. Furthermore, the addition of sodium chloride to the aqueous phase has been observed to reduce agglomeration and particle aggregation. Other suitable salts for this purpose include those soluble in the aqueous phase. Water-soluble salts can be added at concentrations of about 0.1% to about 10% by weight, particularly about 2% to about 5% by weight, and even more particularly about 3% to about 4% by weight.

[0090] Preferably, an organic phase of methyl 2-fluoroacrylate (90 wt%), 1,7-octadiene (5 wt%), and divinylbenzene (5 wt%) is prepared, and 0.5 wt% lauroyl peroxide is added to initiate the polymerization reaction. Separately, an aqueous phase of water, polyvinyl alcohol, phosphate, sodium chloride, and sodium nitrite is prepared. The aqueous and organic phases are mixed together under nitrogen atmosphere while maintaining a temperature below approximately 30°C. Once completely mixed, the reaction mixture is gradually heated with continuous stirring. After initiation of the polymerization reaction, the temperature of the reaction mixture is raised to approximately 95°C. Once the polymerization reaction is complete, the reaction mixture is cooled to room temperature and the aqueous phase is removed. Once water is added to the mixture, the solids can be separated by filtration. The filtered solids are washed with water and then with a methanol / water mixture. The resulting product is a crosslinked (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

[0091] As discussed herein, after polymerization, the product can be hydrolyzed or otherwise deprotected by methods known in the art. To hydrolyze polymers having ester groups to form polymers having carboxylic acid groups, preferably, the polymer is hydrolyzed with a strong base (e.g., sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide) to remove alkyl groups (e.g., methyl groups) and form carboxylates. Alternatively, the polymer can be hydrolyzed with a strong acid (e.g., hydrochloric acid) to form carboxylates. Preferably, the (2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer is hydrolyzed with an excess aqueous solution of sodium hydroxide at a temperature of about 30°C to about 100°C to produce the (2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer. Typically, the hydrolysis reaction is carried out for about 15 to 25 hours. After hydrolysis, the solid is filtered and washed with water and / or alcohol.

[0092] The cation of the polymer salt formed in the hydrolysis reaction or other deprotection steps depends on the base used in that step. For example, when sodium hydroxide is used as the base, a sodium salt of the polymer is formed. This sodium ion can be exchanged with another cation by contacting the sodium salt with an excess of an aqueous solution of a metal salt, yielding an insoluble solid of the desired polymer salt. After the desired ion exchange, the product is washed with alcohol and / or water and dried directly or after dehydration treatment with denatured alcohol; preferably, the product is washed with water and dried directly. For example, the sodium salt of the cation-exchanged polymer can be converted to a calcium salt by washing with a solution in place of sodium, for example by using calcium chloride, calcium acetate, calcium lactate gluconate, or combinations thereof. More specifically, to exchange sodium ions for calcium ions, the (2-fluoroacrylate sodium)-divinylbenzene-1,7-octadiene terpolymer is contacted with an excess of an aqueous solution of calcium chloride to obtain an insoluble solid of a crosslinked (2-fluoroacrylate calcium)-divinylbenzene-1,7-octadiene terpolymer.

[0093] Using this suspension polymerization method, crosslinked polyMeFA polymers are separated in good yields, typically above about 85%, more specifically above about 90%, and even more specifically above about 93%. The second step (i.e., hydrolysis) preferably yields 100%, providing a total yield above about 85%, more specifically above about 90%, and even more specifically above about 93%.

[0094] To add sorbitol to a sorbitol-stabilized composition, the polymer salt is swollen and contacted with a sorbitol solution (e.g., slurryed with an aqueous solution of sorbitol), typically with a slurry containing an excess of sorbitol based on the polymer weight. The slurry is held at ambient temperature and pressure for at least 3 hours. The solids are then filtered off and dried to the desired moisture content.

[0095] Unless otherwise specified, the alkyl groups described herein, either alone or as part of another group, are optionally substituted straight-chain saturated monovalent hydrocarbon groups containing one to twenty carbon atoms, preferably one to eight carbon atoms, or optionally substituted branched saturated monovalent hydrocarbon groups containing three to twenty carbon atoms, preferably three to eight carbon atoms. Examples of unsubstituted alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, etc.

[0096] As used alone or as part of another group herein, the term "aryl" refers to an optionally substituted monovalent aromatic hydrocarbon group, preferably a monovalent monocyclic or bicyclic group containing 6 to 12 carbons in the ring moiety, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl. Phenyl and substituted phenyl are more preferred aryl groups. The term "aryl" also includes heteroaryl groups.

[0097] In the context of terms such as "substituted aryl," "substituted alkyl," etc., the term "substituted" means that in the group under discussion (i.e., the alkyl, aryl, or other group following the term), at least one hydrogen atom bonded to a carbon atom is replaced by one or more substituents, such as hydroxyl (-OH), alkylthio, phosphino, amide (-CON(R)), etc. A (R) B ), where R A and R B Independently hydrogen, alkyl or aryl), amino (-N(R) A (R) B ), where R A and R B Independently, it can be hydrogen, alkyl, or aryl; halogen (fluorine, chlorine, bromine, or iodine); silyl; nitro (-NO2); or ether (-OR). A , where R A It is an alkyl or aryl group, an ester (-OC(O)R) A , where RA It is an alkyl or aryl group, or a ketone (-C(O)R). A , where R A These are alkyl or aryl groups, heterocyclic groups, etc. When the term "substituted" introduces a list of possible substituted groups, it is intended that the term apply to each member of that group. That is, the phrase "optionally substituted alkyl or aryl" should be interpreted as "optionally substituted alkyl or optionally substituted aryl".

[0098] The invention has been described in detail, and it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims.

[0099] Example

[0100] The following non-limiting examples are provided to further illustrate the invention.

[0101] Example 1 Synthesis of methyl 2-fluoroacrylate

[0102] The formation of MFA from DMFM was accomplished in a reactive distillation system. This process is exothermic and kinetically rapid. Several process parameters were optimized, such as the specific reactants, catalyst, and solvent, and their respective concentrations; as well as temperature and pressure. Experimental scales were up to 100 g. Table 1 provides a summary of the test conditions.

[0103] Reactive distillation of DMFM to MFA was carried out in a jacketed 500 mL reactor under mechanical stirring. The boiling product was condensed through a condenser and collected in a three-necked round-bottom flask connected to the reactor. Pressure was controlled by a vacuum pump. Temperature was controlled by a circulator and internal thermocouples. DMFM, solvent, catalyst, and stabilizer were added to the reactor and brought to the desired temperature. Then, paraformaldehyde or formalin was added to the reactor. After the addition of paraformaldehyde or formalin, the temperature was raised to 120°C and the pressure was reduced to 200 mbar (20 kPa). When the liquid no longer condensed (approximately 1 hour), the system was cooled and the vacuum was released.

[0104] Sulfolane (125 g), DMFM (100 g), phenothiazine (1.37 g), and cesium carbonate (21.7 g) were loaded into a jacketed reactor, with mechanical stirring set to 250 rpm. Paraformaldehyde (22 g) was added to the reaction mixture. After exothermic reaction, the reactor jacket temperature was raised to 120 °C, and a vacuum of 200 mbar (20 kPa) was slowly applied. The temperature and pressure were maintained at the set points while the decarboxylation reaction proceeded. The product was collected through a condenser (at -20 °C) into a round-bottom flask in a dry ice and acetone bath. Once no more distillate was collected (approximately 1 hour), the temperature was cooled to 30 °C and the vacuum was released. The distillate was analyzed by GC-MS and GC-FID for identification and quantification, respectively. The receiving flask contained a total of 81.6 g, of which 64.3 g was quantified as MFA, yielding a distillate of 79% pure MFA and a crude yield of 92.7% (Table 1, Condition #20).

[0105] The distillate contained the reaction products, methanol, MFA, and a small amount of solvent. The crude products were identified and quantified by GC-MS and GC-FID, respectively. Acetonitrile was used as the analytical diluent. Only three significant signals were detected in the crude products: MeOH (32 g / mol), MFA (104.1 g / mol), and the solvent. NMR further confirmed the product identity. Quantification of the theoretical yield was achieved using a 5-point GC-FID calibration curve for each identified component.

[0106] Characterization: HNMR, GC-MS, bp.

[0107] Boiling point: 91℃ at 1 bar

[0108] MS: m / z calculated for C4H5FO2: 104.1, measured value [M] + 104.1

[0109] 1 H NMR (500 MHz, CDCl3), δ 5.69 (1H, dd, JH-F = 43.25), 5.3 (1H, dd, J =13), 3.854 (3H, s).

[0110] Table 1: Experimental summary of the one-pot batch method for producing MFA from DMFM

[0111]

[0112] 1 Yield refers to the amount of MFA collected in the distillate pan compared to the theoretical amount that may come from DMFM. The distillate pan contains methanol, MFA, and solvent. MFA is quantified using GC-FID with a 5-point calibration curve. PFA stands for paraformaldehyde, while FA stands for formalin.

[0113] a. Good yield (~76%). More solvent was detected in the distillate pan. NMP accounted for 23a%, compared to 5a% in Example ##14.

[0114] b. Good yield (~85%). Not quantified because the quality of the collection is consistent with Example #18.

[0115] As can be seen from Table 1, conditions 18 to 23 produced the best conversion rates.

[0116] Aldehyde reactants

[0117] Formalin (i.e., a 37 wt% aqueous solution of formaldehyde) and paraformaldehyde were both successful as formaldehyde sources, each yielding good yields. Examples #1 and 9 show that changes in the formaldehyde source do not significantly affect the MFA yield when using equimolar reactant ratios and reaction conditions. Therefore, the addition of water and methanol to formalin does not appear to affect reaction kinetics and yield (Example #1). However, water in the reaction system causes two-phase separation in the distillate receiver, resulting in MFA loss from the organic phase to the methanol-rich aqueous phase. The addition of the formaldehyde source leads to rapid exothermic reaction. When all formaldehyde is added at once, the reaction temperature rapidly increases from 25°C to approximately 60°C. For paraformaldehyde, no benefit was observed in increasing the amount of formaldehyde in the system from a 10% excess to a 70% excess, as seen in Examples #7 and 12.

[0118] Alkali catalyst

[0119] Alkali catalysts, such as potassium carbonate and cesium carbonate, exhibited high yields. Cesium carbonate at a molar ratio of 0.1 was found to be the most effective (Example #21). As shown in Example #10, reducing the molar equivalent to 0.05 resulted in a slight decrease in yield. Example #12 showed that increasing the catalyst molar equivalent did not improve the overall reaction yield. Potassium carbonate produced a slightly lower yield relative to cesium carbonate; this is likely due to the increased solubility of cesium carbonate in aprotic polar solvents (Example #17).

[0120] solvent

[0121] The most effective solvents for the synthesis are polar aprotic solvents with high boiling points, such as N-methyl-2-pyrrolidone (NMP), sulfolane, and dimethyl sulfoxide (DMSO). The polarity of the solvent helps increase the solubility of the carbonate catalyst, and the high boiling point reduces the amount of solvent collected in the distillate receiver. As shown in Table 1, sulfolane is the most effective solvent in terms of yield (Example #21). Additionally, sulfolane produces the purest distillate, likely due to the large boiling point difference between the solvent and the product. When the DMFM concentration is 43 wt%, the solvent NMP produces a good MFA yield (Example #4). The yield decreases slightly when the DMFM concentration is reduced to 30 wt% (Example #5). Experiments using DMSO as a solvent produce lower MFA yields than when using NMP or sulfolane as solvents (Example #6).

[0122] temperature

[0123] Decarboxylation is carried out in the temperature range of 60 to 150 °C. Because the decarboxylation reaction requires heat, very little conversion is observed at lower temperatures (e.g., below 70 °C) (Examples #2, 3, 16), while optimal yields are obtained at 120 °C (Examples #18 to 24). If the reaction temperature reaches 150 °C (Example #15), side reactions may occur, including the self-polymerization of MFA, and more solvent is collected during distillation (Example #15).

[0124] pressure

[0125] When the temperature is increased for decarboxylation, the pressure is reduced to remove CO2 and distill the product. During optimization, the reaction pressure was varied from 50 mbar to atmospheric pressure (1 bar). As can be seen from the data given in the table, the system pressure has little or no effect on decarboxylation kinetics, but it does affect the amount of product distilled from the reaction mixture. Higher yields were obtained at pressures of approximately 200 mbar (Examples #18 to #24). The greater the pressure reduction, the more solvent was detected in the distillate (Examples #14 and #15). At higher pressures of 800 mbar (80 kPa), the yield decreased significantly, as shown in Example #13.

[0126] Example 2 Patiromer sorbitol calcium (i.e., crosslinked (2-fluoroacrylate calcium)-divinylbenzene-1,7-octadiene copolymer loaded with sorbitol)

[0127] 2-Fluoroacrylate (MeFA) was prepared as described in Example 1 above. Divinylbenzene (DVB) was purchased from Aldrich, industrial grade, 80%, a mixture of isomers, and used as is. 1,7-Octadiene (ODE), lauroyl peroxide (LPO), polyvinyl alcohol (PVA) (typical molecular weight 85,000 to 146,000, 87 to 89% hydrolyzed), sodium chloride (NaCl), disodium hydrogen phosphate heptahydrate (Na₂HPO₄·7H₂O), and sodium dihydrogen phosphate monohydrate (NaH₂PO₄·H₂O) were purchased from commercial sources and used as is.

[0128] In a suitably sized reactor equipped with appropriate stirring and other equipment, a monomer-organic phase mixture in a 90:5:5 weight ratio was prepared by mixing methyl 2-fluoroacrylate, 1,7-octadiene, and divinylbenzene. Half of the lauroyl peroxide was added as an initiator for the polymerization reaction. A stable aqueous phase was prepared from water, polyvinyl alcohol, phosphate, sodium chloride, and sodium nitrite. The aqueous and monomer phases were mixed together under nitrogen atmosphere at atmospheric pressure while maintaining a temperature below 30°C. The reaction mixture was gradually heated with continuous stirring. Once the polymerization reaction began, the temperature of the reaction mixture was allowed to rise to a maximum of 95°C.

[0129] After polymerization, the reaction mixture was cooled and the aqueous phase was removed. Water was added, the mixture was stirred, and the solids were separated by filtration. The solids were then washed with water to obtain a crosslinked (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. The crosslinked (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer was hydrolyzed with an excess of aqueous sodium hydroxide solution at 90°C for 24 hours to produce a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. After hydrolysis, the solids were filtered and washed with water. The crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer was exposed to an excess of aqueous calcium chloride solution at room temperature to produce an insoluble crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer.

[0130] Following calcium ion exchange, the wet polymer was slurried with a 25-30% w / w sorbitol aqueous solution at ambient temperature to produce a sorbitol-loaded polymer. Excess sorbitol was removed by filtration. The resulting polymer was dried at 20-30°C until the desired moisture content (10-25 w / w / %) was achieved. This yielded solid petiromer sorbitol calcium (i.e., a sorbitol-loaded crosslinked (2-fluoroacrylate calcium)-divinylbenzene-1,7-octadiene copolymer).

[0131] When describing elements of the invention or its preferred embodiments, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that additional elements may be present besides those listed.

[0132] Based on the above, it can be seen that several objectives of the present invention have been achieved and other advantageous results have been obtained.

[0133] Since various changes can be made to the above compositions and methods without departing from the scope of the invention, all contents contained in the above specification and shown in the drawings should be interpreted as illustrative rather than restrictive.

Claims

1. A method for preparing fluoroacrylate compounds, the method comprising: The compound corresponding to the structure of Formula 1A is contacted with paraformaldehyde or formalin to form a reaction mixture of paraformaldehyde or formalin and the compound corresponding to the structure of Formula 1A. （1A） Each R1 group is a methyl group; and The reaction mixture is heated to a temperature of 110°C to 170°C and a pressure of 100 mbar to 300 mbar in the presence of a base to form a fluoroacrylate compound corresponding to the structure of Formula 2A, wherein the base comprises sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, or combinations thereof. （2A） The total yield of the compounds corresponding to the structure of formula 2A is at least 75% based on the number of moles of the compounds corresponding to the structure of formula 1A.

2. The method for preparing fluoroacrylate compounds according to claim 1, the method comprising: The conversion of the compound corresponding to the structure of Formula 1A to the compound corresponding to the structure of Formula 2A occurs in the same reaction mixture.

3. The method according to claim 1 or 2, wherein the total yield of the compound corresponding to the structure of formula 2A is at least 80% based on the number of moles of the compound corresponding to the structure of formula 1A.

4. The method according to claim 1 or 2, wherein the base comprises cesium carbonate.

5. The method according to claim 1 or 2, wherein the reaction mixture comprises 1 equivalent of the compound corresponding to the structure of formula 1A and more than 1 equivalent of paraformaldehyde.

6. The method of claim 5, wherein the reaction mixture comprises 0.1 equivalent of the base.

7. The method of claim 6, wherein the reaction mixture further comprises a polar aprotic solvent.

8. The method according to claim 1 or 2, wherein the reaction mixture further comprises a solvent, wherein the solvent comprises N-methylpyrrolidone, dimethylimidazolium ketone, sulfolane, or a combination thereof.

9. The method according to claim 1 or 2, wherein the base comprises potassium carbonate, cesium carbonate, or a combination thereof; the temperature is 115°C to 130°C; and the reaction mixture further comprises a solvent comprising N-methylpyrrolidone or sulfolane.

10. The method of claim 9, wherein the compound corresponding to the structure of formula 1A is contacted with paraformaldehyde.

11. A method for preparing patiromer calcium sorbitol, the method comprising: Fluoroacrylates of formula 2A are prepared by the method according to any one of claims 1 to 9; A polymerization reaction mixture comprising divinylbenzene, 1,7-octadiene and a fluoroacrylate of formula 2A is formed to form a crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; The crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer is deprotected to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer; The cross-linked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer was contacted with a calcium salt to form a cross-linked (2-fluorocalcium acrylate)-divinylbenzene-1,7-octadiene polymer; The cross-linked (2-fluoroacrylate calcium)-divinylbenzene-1,7-octadiene polymer is swollen and contacted with sorbitol to form paltiromere calcium sorbitol.

12. The method of claim 11, wherein deprotecting the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer comprises hydrolyzing the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

13. The method of claim 12, wherein hydrolyzing the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer comprises contacting the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a strong base.

14. The method according to claim 13, wherein the strong base comprises sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, or a combination thereof.

15. The method according to any one of claims 11 to 14, wherein contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt to form the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer comprises slurrying the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt.

16. The method of claim 15, wherein the calcium salt comprises calcium chloride, calcium bromide, calcium iodide, or a combination thereof.

17. The method according to any one of claims 11 to 14, wherein swelling of the crosslinked (2-fluorocalcium acrylate)-divinylbenzene-1,7-octadiene polymer comprises slurrying the polymer in a solution containing sorbitol.

18. The method of claim 17, wherein the solution containing sorbitol is an aqueous solution of sorbitol.

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