Synthesis of Methyl 2-Fluoroacrylate

Abstract

Methods for the synthesis of methyl 2-fluoroacrylate (MFA) are provided. The methods involve the use of various hydrofluorinating agents using a variety of starting materials and reaction schemes. Methyl 2-fluoroacrylate prepared by the methods described herein can further be used to prepare patiromer calcium sorbitex.

Description

Technical Field

[0001] A method for synthesizing methyl 2-fluoroacrylate (MFA) is provided.

Background Art

[0002] Methyl 2-fluoroacrylate (MFA) is a raw material for producing various polymer products. The synthetic routes reported in the literature typically produce MFA with low yields and purities and / or are economically infeasible due to reagent costs. Current commercial routes for MFA synthesis involve methyl fluoroacetate (MFAc), a highly toxic starting material. In recent years, a series of new hydrofluoric acid (HF)-based fluorination reagents have been reported, but their applications are limited.

[0003] Accordingly, an object of the present disclosure is to provide an improved process for preparing methyl 2-fluoroacrylate with high purity and high yield without using highly toxic starting materials. The present invention provides a process for preparing methyl 2-fluoroacrylate that is simple, economically feasible, and industrially applicable compared to prior art processes. Specifically, the present disclosure provides a process for preparing methyl 2-fluoroacrylate using a fluorination reagent.

Summary of the Invention

Means for Solving the Problems

[0004] The present disclosure is directed to various processes for preparing fluoroacrylate compounds.

[0005] For example, a process for preparing a fluoroacrylate compound of Formula 2 involves contacting an alkyl propiolate compound of Formula 1 with a fluorinating agent in the presence of a catalyst to form a compound of Formula 2. The compound of Formula 1 corresponds to the following structure,

Chemical Formula

Chemical formula

[0006] Another process for preparing the fluoroacrylate compound of formula 2 involves contacting a compound of formula 4 with a hydrogen fluoride agent in the presence of a Lewis acid catalyst, a strong base, and an alcohol to form a compound of formula 2. The compound of formula 4 corresponds to the following structure,

Chemical formula

Chemical formula

[0007] Yet another method for preparing the fluoroacrylate compound of formula 2A involves contacting a compound of formula 5 with an epoxidizing agent and a fluorinating agent to form a compound of formula 2A. The compound of formula 5 corresponds to the following structure,

Chemical formula

[0008] Another process for preparing the fluoroacrylate compound of Formula 2A involves contacting a compound of Formula 6 with a strong base to form a dehydrofluorination intermediate, and reacting the intermediate with an alcohol, R 1 OH, and a strong acid to form a compound of Formula 2A, wherein the compound of Formula 6 corresponds to the following structure, [Chemistry] In the formula, R 1 is alkyl or aryl, and the compound of Formula 2A corresponds to the following structure, [Chemistry] In the formula, R 1 is defined as above.

[0009] In addition, the present disclosure provides for preparing a fluoroacrylate of Formula 2A by the processes 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, swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting it with sorbitol to form a pachyrhomer calcium sorbitex (i.e., a sorbitol-loaded crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer), and a process for preparing a pachyrhomer calcium sorbitex comprising the same.

[0010] Other objects and features will be in part apparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure relates to routes for the synthesis of methyl 2-fluoroacrylate (MFA) and related compounds.

[0012] This specification provides a methyl propiolate route for the synthesis of MFA and related compounds using a fluorination reagent. This specification also provides a halogen exchange route for the synthesis of MFA and related compounds using a fluorination reagent. This specification also provides a methyl acrylate-epoxide route for synthesizing MFA and related compounds using a fluorination reagent. This specification also provides a difluoropropionic acid (diFPA) route for synthesizing MFA and related compounds using a fluorination reagent.

[0013] Most fluorination reagents are generated from hydrogen fluoride (HF) and typically offer the advantages of low cost and atom efficiency. Organobase-HF complexes such as pyridine / HF complex (“Olah reagent”) and triethylamine / HF complex have been used as nucleophilic fluoride sources. For example, a serine route for MFA synthesis has been reported, using HF-NEt 3 or an HF-pyridine complex to introduce fluorine at the 2-position of 2-amino-3-hydroxypropanoic acid. (Maho, et al. Method of Producing 2-Fluoro-3-Halopropanoic Acid Derivative, JP2014214147 A, 2014)

Chemical formula

[0014] However, the HF-organobase complex has a relatively low HF loading, so a large amount of HF reagent is required. This not only increases the cost but also complicates the purification process. In addition, the regioselectivity and yield of the desired haloacrylate compound vary significantly depending on the HF reagent used.

[0015] Another HF-based fluorination reagent in which 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), a hydrogen bond acceptor, forms a complex with HF has been reported. (OE Okoromoba, et al. Designer HF-Based Fluorination Reagent: Highly Regioselective Synthesis of Fluoroalkenes and gem-Difluoromethylene Compounds from Alkynes. J. Am. Chem. Soc. 2014, 136, 14381-14383.)

Chem.

[0016] The DMPU-HF complex has a higher HF loading than the HF-organic base complex. (65 wt% HF loading, corresponding to an HF:DMPU molar ratio of approximately 11.8:1). The DMPU-HF reagent has been reported to be compatible with cationic metal catalysts and to have high regioselectivity for the monohydrofluorination and dihydrofluorination of alkynes, but its use is limited.

[0017] The DMPU-HF complex has been reported to be acidic enough to activate the imidogold precatalyst (Au-1). In the monohydrofluorination of acceptor-substituted terminal alkynes, the DMPU-HF-Au system was found to produce the inverse Michael addition product as the only regioisomer with good yields. However, purification to remove DMPU after the reaction remains difficult, especially for large-scale synthesis. The DMPU-HF reagent is commercially available through several vendors.

Chem.

[0018] Another HF-based fluorination reagent is the KHSO 4 -HF complex. KHSO 4-HF exists as a liquid stable at room temperature and has the highest HF loading reported (68 wt% HF corresponding to 13 moles of HF per mole of KHSO 4 (Z Lu, et al. Widely Applicable Hydrofluorination of Alkenes via Bifunctional Activation of Hydrogen Fluoride. J. Am. Chem. Soc. 2017, 139, 18202 - 18205)

[0019] The hydrogen - bonding interaction between KHSO 4 and HF improves the nucleophilicity of HF and increases its acidity. This reagent is relatively inexpensive, scalable, easy to handle, and environmentally friendly. It has been applied to the hydrofluorination of alkenes and alkynes. (B Xu, et al. Methods of Hydrofluorination, US20190176134A1, 2019)

[0020] The use of polymer - supported HF complexes as fluorination reagents has also been reported. For example, the inexpensive polymer Amberlite resin has been used as a solid support. Anhydrous HF is absorbed onto the polymer, forming a stable solid HF reagent. The HF loading on the polymer has been reported as 30 wt%. This reagent can be packed into a plastic column and used for hydrofluorination in a continuous - flow process, which can significantly simplify the reaction processing. After the reaction, the resin can be recycled and re - loaded with HF. This reagent is also commercially available through several vendors.

[0021] Alkyl propiolate pathway One process for preparing a fluoroacrylate compound is to contact an alkyl propiolate compound of Formula 1 with a hydrofluorinating agent. The compound of Formula 1 corresponds to the following structure, [Chemical Formula] wherein R 1 is alkyl or aryl. When the compound of Formula 1 contacts the hydrofluorinating agent, a compound of Formula 2A is produced. The compound of Formula 2A corresponds to the following structure, [Chemical Formula] wherein R 1 is alkyl or aryl.

[0022] When the hydrofluorinating agent is a 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) complex with HF (DMPU-HF), R 1 in Formula 1 is methyl.

[0023] For the compound of Formula 1 or Formula 2, R 1 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl, preferably, R 1 can be methyl, ethyl, propyl, or butyl, more preferably, R 1 can be methyl.

[0024] The hydrofluorinating agent can include a 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) complex with HF (DMPU-HF), or a reagent having a structure of Formula 3A, 3B, or 3C (collectively, Formula 3). MHSO 4 -xHF (3A), M 2 SO 4 -xHF (3B), or M a SO 4 -xHF (3C). For Formula 3, M can be Li + Na + K + Rb + Cs + or NH 4 + It can be. Preferably, M is Na + K + or NH 4 + It can be, more preferably, M can be K + It can be.

[0025] For Formula 3C, M a can be Be 2+ Mg 2+ Ca 2+ Sr 2+ Ba 2+ Fe 2+ Zn 2+ Mn 2+ Ni 2+ Co 2+ or Cu 2+ It can be.

[0026] For Formula 3, x can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In addition, x can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. Preferably, x can be 8, 9, 10, 11, 12, 13, or 14 (for example, in Formula 3A), and more preferably, x can be 13.

[0027] MHSO 4 M 2 SO 4 or M a SO 4 has a hydrogen bonding basicity (P) of about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16.

[0028] MHSO 4 M 2 SO 4 or M a SO 4It may also have about 10, about 11, about 12, or about 13 hydrogen-bond basicities (P).

[0029] MHSO 4 , M 2 SO 4 , or M a SO 4 may have a pKa of about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5. Preferably, MHSO 4 , M 2 SO 4 , or M a SO 4 may have a pKa of about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, or about 2.3.

[0030] Any suitable solvent can be used. The solvent may include DCM (dichloromethane), DCE (1,2-dichloroethane), CH 3 CN, DMSO (dimethyl sulfoxide), DMF (dimethylformamide), toluene, or chlorobenzene. Preferably, the solvent is DCE, chlorobenzene, or toluene.

[0031] In particular, MFA can be synthesized by the following reaction by monohydrofluorination of an alkyne using a DMPU-HF reagent and an Au catalyst.

Chemical formula

[0032] Methyl propiolate, the DMPU-HF reagent, and the Au catalyst are combined in the presence of a suitable solvent such as dichloroethane. The mixture is heated at about 50 to about 55 °C for 1 to 3 hours, preferably about 2 hours. The reaction proceeds with a high conversion rate to more than about 80% MFA. The product can be evaluated by HPLC.

[0033] Any suitable solvent can be used. However, solvents with low boiling points such as dichloromethane (DCM) for this reaction need to be avoided because the reaction does not proceed at room temperature. The choice of solvent can also affect the ability to isolate and purify the product. DMPU cannot be removed by aqueous treatment, and distillation is difficult when the boiling point of the solvent is very close to that of MFA. For example, distillation to separate the product MFA from the solvent dichloroethane is difficult due to the boiling points of MFA (91 °C) and DCE (84 °C).

[0034] Furthermore, the reaction does not proceed without a gold (Au) catalyst. Palladium (Pd) catalysts are widely used in the pharmaceutical industry, but elemental Au is cheaper than Pd.

[0035] In addition, MFA can be synthesized by the following reaction through the monohydrofluorination of alkynes using KHSO 4 -13HF reagent and Au catalyst.

Chemical formula

[0036] Methyl propiolate, KHSO 4 -13HF reagent, and Au catalyst are combined in the presence of a suitable solvent such as dichloroethane. The mixture is heated at about 50 to about 60 °C for about 2 to about 4 hours, preferably about 3 hours. The reaction proceeds with a high conversion rate to more than about 85% MFA. The product can be evaluated by HPLC.

[0037] One of the starting materials, methyl propiolate, can be synthesized using acetylene from biomass waste, carbon dioxide (CO 2 ) recovered from waste streams, and methanol (described in U.S. Patent No. 10,131,610B2, 2018, JP Klein. Methods of producing dicarbonyl compound). Methyl propiolate is also commercially available.

[0038] Halogen exchange route The fluoroacrylate compound of Formula 2 can also be prepared by a halogen exchange reaction. For example, a compound of Formula 4 can be reacted with a hydrogen fluoride reagent (e.g., KHSO 4 -13HF), a Lewis acid catalyst, a strong base, and an alcohol to form the compound of Formula 1. The compound of Formula 4 corresponds to the following structure,

Chemical formula

Chemical formula

[0039] Generally, the fluoroacrylate compound of Formula 1 can be prepared by the following reaction scheme, wherein R 2 is hydrogen, alkyl, or aryl, and R 1 is alkyl or aryl.

Chemical formula

[0040] The reaction can be carried out in a stainless steel hydrothermal autoclave reactor equipped with a Teflon (registered trademark) chamber. The reaction is heated, for example, in an oil bath or a dry armored chip bath.

[0041] The Lewis acid catalyst is typically suitable for catalyzing the reaction. For example, SnCl 4 can be used as a Lewis acid catalyst. This catalyst is very hygroscopic. The catalyst can be present at a concentration of about 5 to about 20 mol%. Other suitable Lewis acid catalysts include TiCl 4 , AlF 3 , CuF, or SbF3 is included. However, SbCl 5 did not produce a sufficient amount of the desired product and thus is not suitable as a catalyst.

[0042] The strong base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, rubidium hydroxide, strontium hydroxide, cesium hydroxide, and barium hydroxide.

[0043] The selection of a suitable reaction temperature is important to reduce the formation by the product and improve the conversion. One of the competing reactions is the removal of a chlorine atom to form 2-chloroacrylic acid at high temperature. At 80 °C, the formation of the desired product was not observed, but at 150 °C, 2-chloroacrylic acid was observed as the major product. In the temperature range of 100 - 120 °C, the formation of the desired product was observed by GC / MS.

[0044] For the compound of formula 2, R 2 can be hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or phenyl, preferably, R 2 can be hydrogen, methyl, ethyl, propyl, or butyl, more preferably, R 2 can be hydrogen.

[0045] KHSO 4 The molar ratio of the starting material to the KHSO 4 -13HF reagent is 1 - 0.61. Since the HF content in the reagent is 65 wt%, the molar ratio of HF to dichloropropanoic acid is 7.9 - 1. The conversion of the product can be further improved by increasing the amount of the KHSO

[0046] In particular, MFA can be synthesized according to the following reaction by halogen exchange in a reaction using the KHSO 4 -13HF reagent:

Chemical formula

[0047] In the first step, KHSO 4 -13HF reagent and a Lewis acid catalyst are added to 2,2-dichloropropionic acid to exchange fluorine for chlorine, resulting in 2-chloro, 2-fluoropropionic acid. The use of anhydrous HF for the exchange from Cl to F has been reported. (V Mathieu, et al. Process for the Synthesis of Fluoroorganic Compounds. US 7,304,191 B2, 2007) However, anhydrous HF is a dangerous gas and difficult to handle. Therefore, the use of KHSO 4 -13HF reagent provides the advantages of a stable liquid and high acidity / nucleophilicity.

[0048] There are two routes for forming MFA from the product of Step 1. The first is to use NaOH as a base and water as a solvent to produce 2-fluoroacrylic acid (FAA). This reaction has been reported to have a 90% yield. (V Mathieu, et al. Process for the synthesis of fluoroorganic compounds WO 2002012160, 2002) Then, 2-fluoroacrylic acid (FAA) can be methylated to form MFA. The methylation of FAA has been reported by Tianyu with a 92% yield via the R-21 route. (K Cho, et al. A Kind of Preparation Method of 2-Fluorinated Monomer. CN 107417524B, 2019)

[0049] Alternatively, the methyl ester of the product of Step 1 can be formed prior to HCl removal and can form MFA. The formation of the methyl ester from 2-chloro-2-fluoropropanoic acid can be achieved in one pot after Step 1. The formation of the methyl ester was observed in the preparation of the analytical sample, methanol was added to the crude reaction mixture, and the methyl ester peak was detected by GC / MS. Subsequently, HCl removal (Step 3b) is carried out to form MFA. Similar reactions have been reported in the literature. Typically, an organic base such as triethylamine can drive the removal of HCl and obtain MFA in good yield. (LS Boguslavskaya, et al. Reactions of Halogen Fluorides. IX. Synthesis of α-Fluoroacrylic Scid Serivatives. Zhurnal Organicheskoi Khimii, 1987, 23(6), 1173-7)

[0050] The starting material, 2,2-dichloropropionic acid, can be synthesized in large quantities and at low cost from propionic acid and chlorine. If not recovered, the cost of the catalyst, SnCl 4 can significantly contribute to the overall MFA cost.

[0051] Alkyl acrylate-epoxide route using acidic nucleophilic fluorination reagents KHSO 4 Alkyl acrylate-epoxide route using reagents such as -13HF The fluoroacrylate compound of Formula 2A can be prepared by reacting the acrylate of Formula 5 with a peroxy acid, particularly NaOCl, followed by a hydrofluorination reagent (e.g., KHSO 4 -13HF), removing water, and forming the compound of Formula 2A according to the following reaction.

Chemical formula

[0052] The compound of Formula 5 corresponds to the following structure, [Chemical formula] In the formula, R 1 is alkyl or aryl, and the compound of Formula 2A corresponds to the following structure: [Chemical formula]

[0053] In particular, MFA and related compounds can be synthesized according to the following reaction by the methyl acrylate-epoxide route using the KHSO 4 -13HF reagent. [Chemical formula]

[0054] In the first step, methyl acrylate is epoxidized using standard reagents and procedures. For example, methyl acrylate is reacted with a suitable epoxidizing reagent, such as a peracid, such as meta-chloroperbenzoic acid (m-CPBA), or NaOCl, especially NaOCl, to form a terminal epoxide. This reaction has been reported to exceed an 80% yield. (B Ochiai and T Hirano. Pacile Synthesis of Glycidates via Oxidation of Acrlyates with Aqueous Solution of NaOCl in the Presence of Ammonium Salts, Heterocycles, 2014, 99(2), 487-493). In the second step, the epoxide is then ring-opened using an HF reagent, KHSO 4 -13HF or KHSO 4 -13HF combined with DMPU-HF (Hammond Green Chem., 2019, 21, 1467-1471) to form methyl 2-fluoro-3-hydroxypropanoate with the desired regioselectivity. KHSO 4The use of -13HF has not been reported in the literature.

[0055] In addition to the above two-step procedure, a one-pot synthesis has been reported that directly generates epoxide in situ, followed by generating hydrogen fluoride in one step with a ring-opening reagent (Xu et al., Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins Org. Lett. 2018, 20, 2338 - 2341). Generally, the following reaction scheme illustrates the synthesis of the compound of Formula 2A.

Chemical formula

[0056] KHSO in a one-pot procedure for ring-opening epoxide 4 The use of -13HF has not been reported in the literature. MFA and related compounds can be synthesized by a one-pot route of methyl acrylate - epoxide, first using a suitable epoxidizing reagent, such as a peracid, such as m-CPBA, or NaOCl, especially m-CPBA, and then adding an HF source or reagent to this mixture without isolating the epoxide. Suitable HF sources or reagents are KHSO 4 -13HF (Xu, et al. Org. Lett. 2018, 20, 2338 - 2341), or Selectfluor, especially KHSO 4 -13HF as the ring-opening reagent. A specific reaction scheme for preparing methyl alpha-fluoroacrylate is shown below.

Chemical formula

[0057] The final step, the formation of MFA from 2-fluoro-3-hydroxypropanoate, has been demonstrated on a commercial scale. (M Kreis and J Kirchhoff. Preparation of Substituted 2-Fluoroacrylic Acid Derivatives. US 9,000,210 B2, 2015)

[0058] Based on the proposed mechanism, the use of an epoxide adjacent to an electron-withdrawing group (e.g., a carbonyl group) under strongly acidic conditions results in the formation of a hydroxyl group at the terminal carbon by hydrofluorination of the terminal epoxide, and the addition of fluoride to the 2-position where fluoride is more nucleophilic (A Sattler and G Haufe. High Regioselectivity in the Alternative Aleavage of Terminal Epoxides with Different Sources of Nucleophilic Fluoride. Journal of Fluorine Chemistry, 1994, 69, 185-190). The hydrofluorination mechanism of the terminal epoxide proposed by Sattler et al. is shown in the following scheme.

Chemical formula

[0059] SF 4 The alkyl acrylate-epoxide route using a deoxyfluorination reagent such as a reagent or Fluolead (trademark) (4-tert-butyl-2,6-dimethylphenylsulfatotrifluoride) The fluoroacrylate compound of formula 2A can also be prepared by reacting an acrylate of formula 5 with a peroxy acid, particularly NaOCl, followed by the hydrofluorination reagent of SF 4 to open the epoxide ring, adding a base (e.g., triethylamine), and dehydrofluorinating the intermediate to form the compound of formula 2A. The compound of formula 5 corresponds to the following structure,

Chemical formula

Chemical formula

[0060] Generally, the compound of formula 2A can be prepared according to the following reaction scheme.

Chemical formula

[0061] The important step is step 2, which is the ring-opening of an epoxide using an arylsulfatotrifluoride such as Fluolead (trademark) (Li, L. et al. Deoxyfluorination of alcohols with 3,3-difluoro-1,2 diarylcyclopropenes. Nat. Commun. 7, 13320 (2016)), or a sulfatotrifluoride and its derivatives (SF reagent), especially SF 4 reagent. There is a report (C-LJ Wang. Organic Reactions (Hoboken, NJ) volume 34, 1985) that uses SF 4 in the ring-opening of an epoxide and uses ethyloxirane-2-carboxylate as a starting material in a 53% yield. This report describes the fluorination of oxirane. After the reaction of SF 4 with oxirane, the residue was dissolved in ether and NaF was added to the ether solution. In the present invention, NaF was not used in the post-treatment procedure, but was used directly together with SF 4 A suitable solvent such as DCM can be used. Step 3 was tested using triethylamine as a base.

[0062] Difluoropropionic acid (diFPA) route The fluoroacrylate compound of formula 2A is reacted with a strong base to defluorinate an intermediate compound, followed by R 1It can also be prepared from the acrylate of formula 6 by reacting with OH and a strong acid to form a compound of formula 2A. The compound of formula 6 corresponds to the following structure, [Chemical formula] The compound of formula 2A corresponds to the following structure, [Chemical formula] wherein R 1 is alkyl or aryl.

[0063] The strong base can be sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, rubidium hydroxide, strontium hydroxide, cesium hydroxide, barium hydroxide, sodium methoxide, potassium methoxide, lithium diisopropylamide (LDA), or a combination thereof. Preferably, the strong base includes sodium hydroxide and sodium methoxide.

[0064] Alternatively, the strong base includes LDA.

[0065] The strong acid can be sulfuric acid, phosphonic acid, toluenesulfonic acid, or a combination thereof. Preferably, the strong acid includes sulfuric acid.

[0066] In particular, MFA and related compounds can be synthesized by the difluoropropionic acid route without using HF reagents: [Chemical formula]

[0067] The starting material, difluoropropionic acid, is a solid with a melting point of approximately 41 °C. This compound has been used as a selective herbicide in Japan. (S Watanabe and Y Nomura, α,α-Difluoropropionates as selective herbicide, JP 55069501 A, 1980) Two methods for producing difluoropropionic acid inexpensively have been reported, (a) a method via chlorofluorobutane (A Henne and WJ Zimmerschied. Fluorinated Acid. J. Am. Chem. Soc. 1947, 89, 281 - 283), and (b) a method via pyruvic acid and arylsulfatotrifluoride (e.g., Fluolead (trademark)), or sulfatotrifluoride and its derivatives (SF reagent), especially the SF4 reagent. (C-LJ Wang, 1985) Therefore, the use of difluoropropionic acid offers the advantage of low cost. [Chemical formula]

[0068] In the first step, for dehydrofluorination, difluoropropionic acid is combined with KMnO 4 , KOH, and H 2 O. In the second step, methyl ester formation has been reported in good yield. This reaction requires a strong base, such as sodium methoxide or sodium hydroxide. Weak bases such as sodium carbonate or calcium hydroxide do not function well in this reaction. Dehydrofluorination is very slow at temperatures below 100 °C. At very high temperatures, side reactions such as polymerization reactions will occur. The desired temperature range is approximately 100 °C to approximately 130 °C when DMSO is the solvent and sodium methoxide is the base.

[0069] Polar solvents with high boiling points function well in this reaction. For example, the solvent can be dimethyl sulfoxide (DMSO), water, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMA), or combinations thereof, and preferably, the solvent is DMSO, water, or combinations thereof.

[0070] Since 2-fluoroacrylic acid is highly reactive, at higher concentrations, more polymerization reactions are observed even in the presence of butylated hydroxytoluene (BHT). Lower concentrations of 2-fluoroacrylic acid support reducing side reactions, and overall a large volume is not suitable for large-scale synthesis. A suitable concentration range is from about 1 M to about 2 M.

[0071] In addition, the present disclosure provides for preparing a fluoroacrylate of Formula 2A by the process 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, swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting it with sorbitol to form a pachyrmer calcium sorbitex, and includes a process for preparing a pachyrmer calcium sorbitex.

[0072] The polymerization reaction mixture comprises divinylbenzene, 1,7-octadiene, a fluoroacrylate of Formula 2A, and a polymerization initiator.

[0073] The polymerization initiator includes lauroyl peroxide.

[0074] The method described herein includes hydrolyzing a crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

[0075] The process includes contacting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a strong base to hydrolyze the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

[0076] The strong base is an aqueous strong base.

[0077] The aqueous strong base includes sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, or a combination thereof, and preferably, the aqueous strong base includes sodium hydroxide.

[0078] When a strong base of sodium hydroxide is used, the process includes that the formed (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer is a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

[0079] The process 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, which includes slurrying the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with a calcium salt.

[0080] The process further 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, which further includes slurrying a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt.

[0081] The calcium salt includes calcium chloride, calcium bromide, calcium iodide, or a combination thereof.

[0082] The process further includes swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer by slurrying the polymer in a solution containing sorbitol.

[0083] The solution containing sorbitol is an aqueous sorbitol solution.

[0084] A crosslinked cation exchange polymer (e.g., pachylomer calcium sorbex) 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 generally contains a polymerization suspension stabilizer, a water-soluble salt, water, and optionally a buffer. Then, the organic phase and the aqueous phase are combined and stirred under nitrogen. The mixture is generally heated to about 60°C to about 80°C for about 2.5 to about 3.5 hours, raised to 95°C after polymerization is initiated, 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 a mixture of alcohol / water.

[0085] As described above, a polymerization suspension stabilizer such as polyvinyl alcohol is used to prevent aggregation of particles during the polymerization process. Further, the addition of sodium chloride in the aqueous phase has been observed to reduce aggregation and particle agglomeration. Other salts suitable for this purpose include salts soluble in the aqueous phase. The water-soluble salt can be added at a concentration of about 0.1 wt% to about 10 wt%, specifically about 2 wt% to about 5 wt%, and even more specifically about 3 wt% to about 4 wt%.

[0086] Preferably, an organic phase of methyl 2-fluoroacrylate (90 wt%), 1,7-octadiene (5 wt%), and divinylbenzene (5 wt%) is prepared, 0.5 wt% of lauroyl peroxide is added, and the polymerization reaction is initiated. In addition, an aqueous phase of water, polyvinyl alcohol, phosphate, sodium chloride, and sodium nitrite is prepared. Under nitrogen, the aqueous and organic phases are mixed together while maintaining the temperature below about 30°C. Once fully mixed, the reaction mixture is gradually heated while being continuously stirred. After the polymerization reaction is initiated, the temperature of the reaction mixture is raised to about 95°C. When the polymerization reaction is complete, the reaction mixture is cooled to room temperature and the aqueous phase is removed. When water is added to the mixture, the solid can be isolated by filtration. The filtered solid is washed with water and then with a methanol / water mixture. The resulting product is a cross-linked (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

[0087] As discussed herein, after polymerization, the product can be hydrolyzed by methods known in the art or deprotected by other methods. To hydrolyze a polymer having an ester group to form a polymer having a carboxylic acid group, preferably the polymer is hydrolyzed with a strong base (e.g., sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide) to remove an alkyl (e.g., methyl) group and form a carboxylate salt. Alternatively, the polymer can be hydrolyzed with a strong acid (e.g., hydrochloric acid) to form a carboxylate salt. Preferably, the (methyl 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer is hydrolyzed with an excess aqueous sodium hydroxide solution at a temperature of about 30 °C to about 100 °C to obtain the (sodium 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.

[0088] The cation of the polymer salt formed in the hydrolysis reaction or other deprotection step depends on the base used in that step. For example, when sodium hydroxide is used as the base, the 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 metal salt to obtain the 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 dried after dehydration treatment with denatured alcohol, preferably, the product is washed with water and dried directly. For example, the sodium salt of a cationic ion exchange polymer is converted to a calcium salt by washing with a solution that replaces sodium with calcium, for example, using calcium chloride, calcium acetate, calcium lactate, calcium gluconate, or combinations thereof. More specifically, to exchange sodium ions with calcium ions, a (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer is contacted with an excess of aqueous calcium chloride to obtain an insoluble solid of a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene terpolymer.

[0089] Using this suspension polymerization process, crosslinked polyMeFA polymers are generally isolated in good yields of greater than about 85%, more specifically greater than about 90%, and even more specifically greater than about 93%. The yield of the second step (i.e., hydrolysis) preferably occurs at 100% and the overall yield is greater than about 85%, more specifically greater than about 90%, and even more specifically greater than about 93%.

[0090] Sorbitol is added to the sorbitol-stabilized composition to swell the polymer salt and contacted with a solution of sorbitol (e.g., slurried with an aqueous solution of sorbitol), typically a slurry containing an excess amount of sorbitol based on the weight of the polymer. The slurry is maintained at ambient temperature and pressure for at least 3 hours. The solid is then filtered and dried to the desired moisture content.

[0091] Unless otherwise indicated, an alkyl group described herein either alone or as part of another group is an optionally substituted straight-chain saturated monovalent hydrocarbon radical containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, or an optionally substituted branched saturated monovalent hydrocarbon radical containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples of unsubstituted alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, and the like.

[0092] The term "aryl" as used herein either alone or as part of another group refers to an optionally substituted monovalent aromatic hydrocarbon radical, preferably a monovalent monocyclic or bicyclic group containing 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl. Phenyl and substituted phenyl are more preferably aryl groups. The term "aryl" also includes heteroaryl.

[0093] The terms "about" and "approximately" mean that the exact value is specified or that an approximate value is specified. Thus, for example, "at least about 1,000" is to be interpreted as meaning "at least 1,000" and as meaning "at least approximately 1,000".

[0094] It will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims after the present invention has been described in detail.

Examples

[0095] To further illustrate the present invention, the following non-limiting examples are provided.

[0096] The analytical methods used were thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS).

[0097] The progress of the reaction was monitored by TLC with silica gel plates. The solvent used was a mixture of ethyl acetate, heptane, and toluene in a volume ratio of 3:1:1, respectively, and visualization was carried out under UV (254 nm) or with a KMNO 4 reagent.

[0098] GC-MS analytical method A was used for the analysis of Examples 5 and 7. The following parameters were used. For both Examples 5 and 7: GC instrument: Agilent 7890A; solvent: dichloromethane; column: Agilent HP-5ms; pressure 36 kPa; inlet temperature: 250 °C; injection volume: 1.0 μL; separation 5:1 (Example 5), separation 23:1 (Example 7).

[0099] For Example 5, the temperature parameters were (1) rate 2 °C / min, value 50 °C; (2) rate 10 °C / min, value 240 °C, hold time 10 min.

[0100] For Example 7, the temperature parameters were (1) rate 10 °C / min, value 240 °C, hold time 5 min.

[0101] For GS-MS analytical method A, the further detector parameters were GC / MS: Agilent 597x MSD; ion source: EI; source temperature: 230 °C, quadrupole temperature: 150 °C, fixed electron energy: 70 eV; and scan time segment: time 0.5, start mass 45, end mass 550.

[0102] GC measurement method B. For the GC-FID measurements of Examples 7 and 8, the following method parameters were used. GC instrument: Agilent 6850; solvent: dichloromethane; column: Zebron ZB-5; column pressure: 18 kPa; inlet temperature: 250 °C; injection volume: 1.0 μL; separation 100:1. The temperature parameters were (1) rate 2 °C / min, value 240 °C, hold time 5 min, (2) rate 10 °C / min.

[0103] Example 1: Synthesis of MFA using the methyl propiolate route (DMPU-HF) Methyl propiolate (472.5 mg, 5.62 mmol), 999.38 mg DMPU-HF, 72.11 mg Au catalyst, and 2.5 mL dichloroethane (DCE) were added to a reaction vessel equipped with a stirrer. The reaction temperature was maintained at 55 °C for 3 hours. After completion of the reaction, approximately 90% conversion was observed by HPLC, and the product peak had the same retention time as MFA. The regioselectivity of this reaction will need to be confirmed using 1 1H NMR analysis.

[0104] The DMPU reagent cannot be removed via aqueous treatment. The MFA product can be separated from the DCE solvent using distillation, but this is difficult due to the close boiling points of MFA (91 °C) and DCE (84 °C) (OE Okoromoba, et al. 2014, S7 (Supplementary Information))

[0105] Example 2: Synthesis of MFA using the methyl propiolate route (KHSO 4 -13HF, Au catalyst) Methyl propiolate (84.07 mg, 1.0 mmol) in DCE, 198 mg KHSO 4 -13HF, 1 mL of 0.01 M Au catalyst, and 1 mL dichloroethane (DCE) were added to a reaction vessel equipped with a stirrer. The reaction temperature was maintained at 55 °C for 3 hours. After completion of the reaction, approximately 85% conversion was observed by HPLC, and the product peak had the same retention time as MFA. The regioselectivity of this reaction will also 1 be confirmed using 1H NMR analysis.

[0106] In a comparative reaction without the Au catalyst, the MFA product was not observed by HPLC.

[0107] Example 3: Synthesis of MFA precursor using the halogen exchange route The reactants were combined in a stainless steel hydrothermal autoclave reactor equipped with a Teflon chamber. The chamber was equipped with a stir bar and the reactants were sealed in the autoclave reactor. The reactants were heated in an oil bath or a dry armor chip bath. The reactor did not have an internal temperature control so the external bath temperature was recorded.

[0108] SnCl 4 was used as Lewis acid catalyst in a molar ratio of 0.18 to the starting material. At 80°C, no formation of the desired product was observed, whereas at 150°C, 2-chloroacrylic acid was observed as the major product. In the temperature range of 100-120°C, formation of the desired product was observed by GC / MS.

[0109] KHSO 4 The molar ratio of the starting material to the -13HF reagent was 1 to 0.61. The HF content in the reagent was 65 wt %, so the molar ratio of HF to dichloropropanoic acid was 7.9 to 1.

[0110] Example 4: Methyl acrylate-epoxide route (KHSO in DCE 4 Synthesis of MFA precursor using -13HF The first step, the synthesis of methyl oxirane-2-carboxylate, was reported in 80% yield (B Ochiai and T Hirano, 2014). Methyl oxirane-2-carboxylate (102 mg, 1 mmol) was dissolved in 2 mL of DCE and cooled to 0 °C. KHSO 4 -13HF (435 mg, 1.1 mmol) was added dropwise to the solution with stirring. The reaction was stirred at room temperature overnight. Both starting material and the epoxide ring-opened product were observed. The GC retention time of the epoxide ring-opened product matched the retention time of the desired product, methyl 2-fluoro-3-hydroxypropanoate. In addition, an impurity with a higher retention time was observed, which is a possible product from epoxide polymerization.

[0111] Example 5: Methyl acrylate-epoxide route (KHSO4 Synthesis of MFA Precursor Using -13HF, NEET Methyloxirane-2-carboxylate (5.0 g, 49 mmol) was added into a PTFE vial and cooled to 0 °C. KHSO 4 -13HF (3.04 g, 7.7 mmol, KHSO4-13HF reagent, meaning 2.03 equivalents of HF (99.57 mmol HF)) was added dropwise to the solution with stirring. The reaction mixture was stirred at room temperature overnight for 21 hours. Then, the crude solution was poured onto ice and basified with saturated KHCO 3 solution. The phases were extracted three times with dichloromethane. The organic layers were combined. After GC-MS measurement, the desired product methyl 2-fluoro-3-hydroxypropanoate (retention time 14.0 minutes) was obtained. In addition to the desired product, potential positional isomer methyl 3-fluoro-2-hydroxypropanoate (retention time 9.4 minutes) and an unknown epoxide ring-opening / elimination product (retention time 17.4 minutes) were observed. The desired product was compared with the reference standard GC-MS spectrum of methyl 2-fluoro-3-hydroxypropanoate.

[0112] Analysis Method A: MS (GC / MS, 70 eV, EI) m / z [fragment]: 121 [C 4 H 6 FO 3 + , 92 [C 3 H 5 FO 2 .+ , 77 [C 3 H 6 FO + , 63 [C 2 H 4 FO + , 60 [C 2 HFO .+ , 59[C 2 H 3 O 2 + , 46 [C 3 H 5 FO 2 2+ .

[0113] Example 6: Synthesis of MFA Precursor Using One-Pot Methyl Acrylate-Epoxide Route (m-CPBA and KHSO 4 -13HF) A PTFE vial was loaded with 77% w / w m-CPBA (900 mg, 4 mmol, 2 eq). DCM (20 mL) was added and the resulting solution was cooled in an ice bath. After 30 minutes, methyl acrylate (2 mmol) was added, followed by KHSO4-13HF (400 μL 0.67 mmol, 0.33 eq of KHSO4-13HF or 4.4 mmol of HF) as the HF source. The reaction mixture was stirred at room temperature overnight. After stirring, it was poured onto ice, basified with saturated KHCO 3 solution and stirred for an additional 30 minutes. The reaction mixture was then extracted with DCM (3 × 50 mL), the combined organic layers were dried over MgSO 4 and filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using a suitable mixture of heptane and ethyl acetate as the eluent (7:3, R f (desired product) = 0.4, R of the purchased reference substance methyl 2-fluoro-3-hydroxypropanoate f which was consistent). In addition to the formation of the desired product, methyl glycidate (starting material) and potential positional isomers were obtained.

[0114] R f (methyl 2-fluoro-3-hydroxypropanoate) = 0.4 (ethyl acetate:heptane:toluene, 3:1:1)

[0115] Example 7: Synthesis of Methyl 2,3-Difluoropropionate Using Methyl Acrylate-Epoxide Route (SF 4 ) A 250 ml stainless steel autoclave was charged with the autoclave with SF 4Before pressurizing with (2 weight equivalents of methyl glycidate, 44.3 g, 0.41 mol, 2.1 equivalents), methyl glycidate (20 g, 0.20 mol, 1.0 equivalent) was loaded as a solution in DCM (20 mL), and the reagent NaF (10.3 g, 0.25 mol, 1.25 equivalents) was loaded internally. After heating the reaction mixture at 85 °C for 12 hours, it was quenched with ice-cooled KHCO 3 Quenched with ice-cooled KHCO 3 After quenching with the solution, NMR, GC-FID, and GC-MS analyses confirmed incomplete consumption of the starting materials (58.3% by GC-FID, method B). High-boiling by-products and multiple minor by-products (approx. 18% area by GC-FID, method B) were observed by GC-FID, but the desired adjacent difluoride product, methyl 2,3-difluoropropionate, was observed (24.0% area by GC-FID, method B).

[0116] Analysis method A: Retention time in GC / MS analysis: methyl 2,3-difluoropropionate = 4.85 min, methyl glycidate = 7.69 min

[0117] MS (GC / MS, 70 eV, EI) m / z [fragment]: 123 [C 4 H 5 F 2 O 2 + , 93 [C 3 H 3 F 2 O + , 91 [C 3 H 4 FO 2 + , 73.0 [C 3 H 5 O 2 + , 65 [C 2 H 3 F 2 + , 59 [C 2 H 3 O 2 + , 46 [C 3 H 5 FO 22+ .

[0118] Example 8: Synthesis of MFA using Example 7 and triethylamine as a base A solution of the difluoro compound methyl 2,3-difluoropropionate (0.5 g, 4.0 mmol, 1 equiv) of Example 7, triethylamine (0.49 g, 0.67 mL, 4.8 mmol, 1.2 equiv), and BHT (4.9 mg, 0.02 mmol, 0.0055 equiv) in DCM (20 mL) was stirred at 37 °C for 87 h. The reaction was quenched and the solvent was removed under atmospheric distillation. In addition to the starting material methyl 2,3-difluoropropionate (GC-FID, retention time 4.3 min by method B) and BHT (GC-FID, retention time 12.2 min by method B), the desired product MFA (GC-FID, retention time 3.5 min by method B) was found. The MFA obtained was compared with a reference standard of MFA.

[0119] Example 9: Synthesis of MFA using the difluoropropionic acid (diFPA) route Difluoropropionic acid (0.5 g, 4.5 mmol) was dissolved in 2 mL of DMSO. Sodium methoxide (0.74 g, 13.6 mmol) was added to the solution. The reaction mixture was stirred at 120 °C for 3 h and the formation of 2-fluoroacrylic acid was observed. Methanol (CH 3 OH) and sulfuric acid (H 2 SO 4 ) were added to 2-fluoroacrylic acid to produce MFA. (K Cho, et al., 2019)

[0120] Example 10: Pachymar calcium sorbitex (i.e., sorbitol-loaded, cross-linked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer) Methyl 2-fluoroacrylate (MeFA) is prepared as in Example 1 above. Divinylbenzene (DVB) is purchased from Aldrich, technical grade 80%, a mixture of isomers, and used as received. 1,7-Octadiene (ODE), lauroyl peroxide (LPO), polyvinyl alcohol (PVA) (typical molecular weight 85,000 - 146,000, 87 - 89% hydrolysis), sodium chloride (NaCl), disodium hydrogen phosphate heptahydrate (Na 2 HPO 4 ·7H 2 O), and sodium dihydrogen phosphate monohydrate (NaH 2 PO 4 ·H 2 O) are purchased commercially and used as received.

[0121] In a reactor of appropriate size equipped with suitable stirring and other apparatus, a 90:5:5 weight ratio mixture of the organic phase of the monomers is prepared by mixing methyl 2-fluoroacrylate, 1,7-octadiene, and divinylbenzene. Half of the lauroyl peroxide is added as an initiator for the polymerization reaction. A stabilized aqueous phase is prepared from water, polyvinyl alcohol, phosphate, sodium chloride, and sodium nitrite. The aqueous phase and the monomer phase are mixed together under atmospheric nitrogen while maintaining the temperature below 30°C. The reaction mixture is gradually heated while continuously stirred. When the polymerization reaction is initiated, the temperature of the reaction mixture is raised to a maximum of 95°C.

[0122] After the polymerization reaction is completed, the reaction mixture is cooled and the aqueous phase is removed. Water is added, the mixture is stirred, and the solid material is isolated by filtration. The solid is 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 is hydrolyzed with an excess aqueous sodium hydroxide solution at 90 °C for 24 hours to obtain a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer. After hydrolysis, the solid is filtered and washed with water. The crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer is exposed to an excess aqueous calcium chloride solution at room temperature to obtain an insoluble crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer.

[0123] After calcium ion exchange, the wet polymer is slurried with a 25-30% w / w aqueous solution of sorbitol at ambient temperature to obtain a sorbitol-loaded polymer. The excess sorbitol is removed by filtration. The resulting polymer is dried at 20-30 °C until the desired water content (10-25 w / w%) is reached. Thereby, a solid pachylomer calcium sorbitex (i.e., sorbitol-loaded, crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene copolymer) is obtained.

[0124] When introducing an element of the present invention or a preferred embodiment thereof, the articles "a", "an", "the", and "said" are intended to mean that one or more of the elements are present. The terms "comprising", "including", and "having" are intended to be inclusive and to mean that there may be additional elements other than the recited elements.

[0125] In view of the above, it will be appreciated that some of the objects of the present invention are achieved and other advantageous results are achieved.

[0126] Without departing from the scope of the present invention, various changes can be made to the above compositions and processes. Therefore, all matters included in the above description and shown in the accompanying drawings are intended to be construed not in a limiting sense but as illustrative. For example, the present invention provides the following items. (Item 1) A process for preparing a fluoroacrylate compound of Formula 2A, comprising contacting a compound of Formula 5 with an epoxidizing agent and a fluorinating agent to form said compound of Formula 2A, wherein said compound of Formula 5 corresponds to the following structure,

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

1. A process for preparing a fluoroacrylate compound of Formula 2A, comprising contacting a compound of Formula 5 with an epoxidizing agent and a fluorinating agent, removing water to form said compound of Formula 2A, wherein said compound of Formula 5 corresponds to the following structure, 【Chemical 34】 wherein, R １ is alkyl or aryl, said compound of Formula 2A corresponds to the following structure, 【Chemical 35】 wherein, R １ is defined above, said fluorinating agent comprises KHSO₄-13HF, process.

2. A process for preparing a fluoroacrylate compound of Formula 2A, comprising contacting a compound of Formula 5 with an epoxidizing agent and a fluorinating agent, dehydrofluorinating to form said compound of Formula 2A, wherein said compound of Formula 5 corresponds to the following structure, 【Chemical 34】 wherein, R₁ is alkyl or aryl, said compound of Formula 2A corresponds to the following structure, 【Chemical 35】 wherein, R₁ is as defined above, said fluorinating agent comprises SF₄, dehydrofluorination comprises adding a base, process.

3. The process according to Claim 2, wherein said fluorinating agent further comprises NaF.

4. The process according to any one of Claims 1 to 3, wherein said compound of Formula 5 is reacted with said epoxidizing agent to form a terminal epoxide group, and then reacted with said fluorinating agent to open the epoxide ring.

5. The process according to any one of Claims 1 to 4, wherein said reaction of said compound of Formula 5 with said epoxidizing agent and said fluorinating agent is carried out in one vessel.

6. The process according to any one of Claims 1 to 5, wherein said epoxidizing agent is NaClO.

7. The process according to any one of Claims 1 to 5, wherein said epoxidizing agent is meta-chloroperbenzoic acid.

8. R １ is C １ -C ６ alkyl, the process according to any one of claims 1 to 7.

9. R １ is C １ -C ３ alkyl, and the process according to any one of claims 1 to 7.

10. R １ The process according to any one of claims 1 to 7, wherein R is methyl or ethyl.

11. R １ The process according to any one of claims 1 to 7, wherein R is methyl.

12. A process for preparing pachylomer calcium sorbitex, comprising preparing said fluoroacrylate of Formula 2A by the process according to any one of Claims 1 to 11, forming a polymerization reaction mixture comprising divinylbenzene, 1,7-octadiene, and said 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, Swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer and contacting it with sorbitol to form a pachyrmer calcium sorbitex, a process comprising.

13. The process according to claim 12, wherein the polymerization reaction mixture comprises divinylbenzene, 1,7-octadiene, the fluoroacrylate of formula 2A, and a polymerization initiator.

14. The process according to claim 13, wherein the polymerization initiator comprises lauroyl peroxide.

15. The process according to any one of claims 12 to 14, wherein deprotecting the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer to form a crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer comprises hydrolyzing the crosslinked alkyl (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

16. The process according to claim 15, 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.

17. The process according to claim 16, wherein the strong base is an aqueous strong base.

18. The process according to claim 17, wherein the aqueous strong base comprises sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, or a combination thereof.

19. The process according to claim 18, wherein the aqueous strong base comprises sodium hydroxide.

20. The process according to claim 19, wherein the formed (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer is a crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer.

21. The process according to any one of claims 12 to 19, wherein contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt to form a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer includes slurrying the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt.

22. The process according to claim 19, wherein contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt to form a crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer includes slurrying the crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer with the calcium salt.

23. The process according to any one of claims 12 to 22, wherein the calcium salt includes calcium chloride, calcium bromide, calcium iodide, or a combination thereof.

24. The process according to any one of claims 12 to 23, wherein swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1,7-octadiene polymer includes slurrying the polymer in a solution containing sorbitol.

25. The process according to claim 24, wherein the solution containing sorbitol is an aqueous sorbitol solution.

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