Novel synthesis of methyl-2-fluoroacrylate

Abstract

The present invention relates to novel synthesis methods of methyl 2-fluoroacrylate (MFA) which is a key precursor for the production of Veltassa® (Patiromer). The methods according to the invention are conducted by reacting an α-substituted β-hydroxy propionic acid derivative (I) via one or more intermediate steps involving one or more α-, β-substituted propionic acid derivatives (II) to obtain MFA (III).

Description

NOVEL SYNTHESIS OF METHYL 2-FLUOROACRYLATEINTRODUCTIONThe present invention relates to novel synthesis methods of methyl 2- fluoroacrylate (MFA) which is a key precursor for the production of Veltassa® (Patiromer). The methods according to the invention are conducted by reacting an a- substituted p-hydroxy propionic acid derivative (I) via one or more intermediate steps involving one or more a-, p-substituted propionic acid derivatives (II) to obtain MFA (III).BACKGROUND OF THE INVENTION AND PRIOR ARTVeltassa® is a medication for the treatment of hyperkalemia, a condition afflicting the metabolization of potassium, which results in elevated potassium levels in the blood. It was approved by the US based Federal Drug Administration in 2015 and by the European Medicines Agency in 2017. The production of this important active pharmaceutical ingredient requires the crosslinking polymerization of methyl 2- fluoroacrylate (III) with commonly available dienes.MFA Common Crosslinkers Patiromer Monomer UnitWhile the Veltassa® synthesis can be regarded as safe, MFA (III) as a compound is hazardous and so is its production. Many of the established approaches to synthesize MFA (III) depend on toxic precursors, difficult to handle fluorination agents in largeamounts and / or energetically costly synthesis or purification protocols. In the past, manifold inventions involving halogen acetates have been brought forth.Methods for the production of MFA were established as early as in the 1960’s. In the 1963 application US03075002A fluoro acetates are reacted with aldehydes in the presence of strong bases to yield MFA (III). Its follow-up inventions, US03262967A and US03262968A, offer alternative synthesis routes, modifying the fluoro acetate route by substitution of aldehydes with alkyl formates or dialkyl oxalates respectively. All of these proposed processes depend on fluoro acetates, which are highly toxic and harmful to the environment.Also, the process described in CN104478715A, makes use of halogen acetates, which are reacted with methyl oxalate.EP02864286B1 describes a process based on using low-boiling alkanes as solvents for the reaction and isolation of MFA (III), wherein the problem of hazardous precursors is not addressed and the addition of low boiling alkanes to the synthesis provides new health risks.Next to the well-established halogen acetate routes, MFA (III) synthesis approaches starting from other precursors were developed as well.An example for this is W02013003495A2, where unsubstituted acrylates serve as the starting material. These structurally simple acrylates are non-toxic, but they readily polymerize which requires careful handling and the acrylates still pose an environmental hazard. Another problem is the direct fluorination of the double bond with gaseous fluorine, which can be deemed a considerable risk.In contrast, in WO2021191876A1 , acrylates or propiolates are treated with KHSO4-13HF as a fluorination agent or a-difluoro propionic acid is singly defluorinated with a strong base to produce MFA (III).Furthermore, synthesis procedures comprising malonate derivatives have been employed. Said routes make use of the leaving group potential of larger molecular residues inherent or introduced to the precursor.The application EP3157900A1 discloses how halogen malonates can be hydroxymethylated with formaldehyde. The reaction product is further reacted to substitute the hydroxy group with a different leaving group such as another halogen group or a chlorosulfinyloxymethyl group and subsequently reactively distilled to obtain MFA (III). However, the reintroduction of formaldehyde can be considered disadvantageous from a health point of view.A process starting from the same type of precursor is presented in WO2021097012A1. There are high temperatures necessary to conduct the reactive distillation step necessary to obtain MFA (III), thus improvement in terms of cost reduction is desirable.Also related to EP3157900A1 is the invention WO2010149683A1 , but a different type of precursor is applied. Instead of starting the synthesis from a fluorinated malonate, an a-fluoro p-halogen propionaldehyde derivative produced from an a-fluoro p-hydroxy propionaldehyde derivative is the key compound. This route involves the isolation of the a-fluoro p-halogen propionaldehyde derivative, which is again potentially nonbeneficial for the health of working professionals.Another approach in the production of MFA (III) is described in US3839170A. Here, amino acid D-alanine is fluorinated using perfluoro compounds and ionizing radiation to fluorinate the amino acid.Generally, methods for the possible fluorination of amino acids are disclosed in the literature in publications by Morin et al.; Synthesis; 1987; 1987(5); 479 - 480, Hamman et al.; Tetrahedron Lett.; 1983; 24(1); 57 - 60, Olah et al.; Synthesis; 1974; 1974(9); 654 - 655 and Olah et al.; J. Org. Chem.; 1979; 44(22); 3872 - 3881 .These papers describe approaches to diazotize the amino group in small amino acid derivatives. Subsequent to the diazotization step, a fluorination agent, commonly the so-called Olah's reagent, is applied to introduce the fluorine group at the selected position via a nucleophilic substitution. The applied fluorination agent, Olah’s reagent, which is hydrofluoric acid in pyridine, is easily handleable compared to gaseous fluorine.In JP2014214147A this fluorination method is used to produce MFA (III), starting from a p-substituted a-amino acid derivative. In principle, the advantage to this approach would primarily be that working professionals are not exposed to dangerous precursors at all, relying on easily handleable amino acids such as L-Serine instead. Furthermore, JP2014214147A proposes the introduction of a leaving group on the p-position of the amino acid derivative to facilitate its elimination. However, in practice, it turned out that the synthesis established in JP2014214147A did not work as described therein.In summary, the synthesis routes known from the prior art lack a continuously safe approach in the production of MFA (III). Working professionals are either exposed to hazardous precursors, isolated intermediates, solvents or fluorination agents. They are furthermore disadvantageous by their inefficiency, as the reaction steps require long durations or high temperatures to produce intermediates of MFA (III).OBJECT OF THE INVENTIONThe present invention aims to provide alternatives to the established synthesis routes for MFA (III) which overcome the above-described disadvantages. In particular, it was an object of the invention to provide a new synthesis route for MFA (III), which minimizes the exposure to harmful substances for the working professional and reduces energy costs during the production of MFA (III). A further goal of the present invention is the establishment of providing methods using readily available starting materials such as easily handleable amino acids in the synthesis of MFA (III). It is attempted to limit theprocess to the least risky precursors and avoid intermediate isolation by developing reactions which can be carried out as a without a need for any intermediate purification steps were possible. Furthermore, this increases the processes efficacy in terms of time investment. The inventors surprisingly found that when using amino acids as precursors it becomes possible to form harmless intermediate amino acid salts in the production of MFA (III) which facilitate in situ formation of relevant precursors without the need for their isolation. In a further aspect, the inventors surprisingly found that the in situ conversion of amino acids to a-fluorinated organic acids via diazotization can be carried out with liquid diazotization agents which are easier to charge into the reactor.In a further aspect of the invention, it is aimed to introduce excellent leaving groups into possible precursors for MFA (III), thus reducing energy cost for elimination reactions through easier elimination of said group in a viable production route of MFA (III). The inventors surprisingly found that anhydrides of organic acids can be energy efficiently introduced to common propionic acid derivatives to produce substituted or unsubstituted alkoxy- or aryloxycarbonyl groups thereon, which serve as excellent leaving groups in the production of MFA (III).SUMMARY OF THE INVENTIONThe inventors of the present invention developed a new method for providing MFA in a safe and efficient manner with high yields. A further aspect of the invention relates to the preparation of patiromer calcium sorbitex using the method described herein.The present invention includes, without being limited thereto, the following aspects:[1] A process for preparing methyl 2-flouro acrylate (III) comprising a reaction of a precursor of the general formula (I), to provide an intermediate of the general formula (II):(I) (II) (III) whereinR1is a leaving group comprising a halogen group, a pseudohalogen group or a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.[2] The process according to [1], wherein precursor (I) is a precursor (la) which is characterized throughR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is an amino group; and intermediates of the formula (II) are characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs'alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.[3] The process according to [1] or [2], wherein the precursor (la) is a precursor (la’):[4] The process according to any one of [1] to [3], wherein the precursor (I, la) is reacted to provide an intermediate (Ila) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a diazo substituent or an amino group.[5] The process according to any one of [1] to [4], wherein the intermediate (Ila) is an intermediate (Ila’) or an Intermediate (Ila”):[6] The process according to any one of [1] to [4], wherein said reaction comprises a halogenation or a pseudohalogenation and optionally the introduction of a protecting group before the halogenation or the pseudohalogenation and the removal of the protecting group after the halogenation or the pseudohalogenation to form the intermediate (II, Ila, Ila’, Ila”).[7] The process according to [6], wherein the intermediate (II, Ila, Ila’ Ila”) is further reacted to a second intermediate (lib) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen; andX is a fluoro substituent.[8] The process according to [7], wherein the second intermediate (lib) is an intermediate (lib’):(Hb’).[9] The process according to [7] or [8], wherein the reaction of the intermediate (Ila, Ila’, Ila”) to the second intermediate (lib, lib’) comprises a fluorination step using a fluorination agent, and a diazotization step using a diazotization agent, and optionally an aqueous work up.

[0010] The process according to any one of [7] to [9], comprising a fluorination step using a fluorination agent comprising HBF4, hexafluorophosphates (PF6-), hexafluoroantimonates (SbF6-) and / or Olahs reagent.

[0011] The process according to

[0010] , wherein Olah’s reagent is used as a fluorination agent.

[0012] The process according to

[0010] or

[0011] , wherein Olah’s reagent is used with a pyridine to HF ratio of 25:75 to 50:50, preferably with a ratio of 30:70.

[0013] The process according to any one of [7] to

[0012] , comprising a diazotization step using a diazotizing agent such as HNO2, NaNO2, tert-butyl nitrite and / or mixtures thereof, preferably NaNO2 and / or tert-butyl nitrite.

[0014] The process according to

[0013] , wherein NaNC>2 is used as a diazotization agent.

[0015] The process according to

[0014] , wherein the diazotization and fluorination step is carried out at temperature ranges between -20 °C to 10 °C, preferably between -20 °C and -10 °C.

[0016] The process according to

[0013] , wherein tert-butyl nitrite is used as a diazotization agent.

[0017] The process according to

[0016] , wherein the diazotization is carried out between -10 °C and 20 °C, preferably between -10 °C and 0 °C.

[0018] The process according to any one of [9] to

[0017] , wherein the aqueous work-up is carried out after the fluorination step and comprises the addition of an anhydrous alkali fluoride, preferably anhydrous KF, to the reaction mixture.

[0019] The process according to any one of [1] to

[0018] , wherein the second intermediate (lib, lib’) is further reacted via an esterification to form a third intermediate (He) wherein:R1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is a methyl substituent; and X is a fluoro substituent.

[0020] The process according to

[0019] , wherein the third intermediate (He) is an intermediate (He’):

[0021] The process according to any one of [1] to

[0020] , wherein the formation of the intermediate (He, He’) is carried out starting from the intermediate (Ha, Ha’, Ha”) via the intermediate (I lb, Hb’) without isolation of the intermediates (I lb, Hb’).

[0022] The process according to any one of [1] to

[0021] , comprising a step of reactive distillation for preparing and isolating MFA (HI) from the intermediates.

[0023] The process according to [1], wherein the precursor (I) is a precursor (lb) and is characterized throughR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent; andIntermediates of the formula (II) are intermediates (Hd) characterized through R1is a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent.

[0024] The process according to

[0023] , wherein the precursor (lb) is a precursor (lb’) and intermediate (lid) is an intermediate (lid’):(lb’) (lid’).

[0025] The process according to any one of

[0023] to

[0024] , wherein the precursor (I, lb, lb’) is reacted with an organic acid anhydride (IV):whereinR3and R3’ are the same or different and independently represent the same or different organic leaving groups.

[0026] The process according to

[0025] , wherein the organic acid anhydride (IV) is TFAA:(TFAA).

[0027] The process according to

[0023] to

[0026] , wherein the reaction between precursor (I, lb, lb’) and the organic acid anhydride (IV) is conducted in an organic aprotic solvent selected from dichloromethane, dichloroethane and carbon tetrachloride, preferably dichloromethane.

[0028] The process according to any one of

[0023] to

[0027] which is conducted at a temperature below 30 °C, preferably at a temperature between 15 °C and 25 °C, more preferably at room temperature (20 °C ± 3 °C).

[0029] The process according to any one of

[0023] to

[0028] which is conducted in a time period of 1 h to 6 h, preferably 4 h.

[0030] The process according to any one of

[0023] to

[0029] , comprising a step of an elimination for preparing and isolating MFA (III) from the intermediates.

[0031] The process according to

[0030] , wherein the elimination to obtain MFA (III) from the intermediates is conducted at a temperature of less than 100 °C, preferably at a temperature between 50 °C and 70 °C, more preferably at 60 °C.

[0032] The process according to

[0030] or

[0031] , wherein the elimination to obtain MFA (III) from the intermediates is conducted from 15 min to 45 min, preferably for 30 min.

[0033] A process for preparing patiromer calcium sorbitex comprising,(i) preparing methyl 2-fluoro acrylate (III) by the process according to any one of [1] to

[0032] , and(ii) forming a polymerization reaction mixture comprising divinyl benzene, 1 ,7-octadiene and the MFA (III) to form crosslinked alkyl(2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer;(iii) deprotecting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer to form crosslinked (2-fluoroacrylate)-divinylbenzene- 1 ,7-octadiene polymer; and(iv) contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer with a calcium salt to form crosslinked (calcium 2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer; and(v) swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer and contacting with sorbitol to form patiromer calcium sorbitex.

[0034] The process according to

[0033] , wherein the polymerization reaction mixture comprises divinyl benzene, 1 ,7-octadiene, the MFA (III) and a polymerization initiator, which is preferably lauroyl peroxide.

[0035] The process according to

[0033] or

[0034] , wherein deprotecting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer to form crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer comprises hydrolyzing the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer.

[0036] The process according to any one of

[0033] to

[0035] , 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 selected from sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide or combinations thereof, preferably with sodium hydroxide.

[0037] The process according to any one of

[0033] to

[0036] , wherein the (2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer formed is crosslinked (sodium 2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer.

[0038] The process according to any one of

[0033] to

[0037] , wherein contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer with a calcium salt to form crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer comprises slurrying the crosslinked (2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer with a calcium salt.

[0039] The process according to any one of

[0033] to

[0038] , wherein the calcium salt comprises CaCh, CaBr2, or Cal2 or a combination thereof.

[0040] The process according to any one of

[0033] to

[0039] , wherein the swelling of the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer comprises slurrying the polymer in a solution comprising sorbitol, preferably in an aqueous sorbitol solution.The present invention is described in more detail as follows.DETAILED DESCRIPTION OF THE INVENTIONI. Precursors and IntermediatesIn the process of the invention as described herein methyl 2-flouro acrylate / MFA (III) is prepared by reaction of a precursor of the general formula (I) via one or more intermediates, which may be summarized under the general formula (II):(I) (II) (HI)A precursor in the sense of the present invention relates to a central starting compound at the beginning of the process steps described herein. An intermediate in the sense of the present invention describes a product resulting from any of the reaction steps conducted on a precursor (I) involved in the process and being further reacted to finally provide MFA (III).In the process of the invention, intermediates do not necessarily need to be isolated, but may occur in the reaction mixture and can from thereon be processed further without additional or with a reduced amount of purification steps. Such a reactionprocedure allows for quicker production of the desired product and less exposure to the intermediates for working personnel.In the sense of the invention a-substituted, p-hydroxy propionic acid derivatives serve as precursors that correspond to the general formula (I) and a, p-substituted propionic acid derivatives serve as intermediates that correspond to the general formula (II).(I) (II)(precursor) (intermediates) whereinR1is a leaving group comprising a halogen group, a pseudohalogen group or a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.In one embodiment of the invention, the a-substituted, p-hydroxy propionic acid precursor (I) is indicated as precursor (la), wherein preferablyR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is an amino group.A particularly preferred embodiment of the precursor (I, la) is the precursor (la’):In another embodiment of the invention, the a-substituted, p-hydroxy propionic acid precursor (I) is indicated as precursor (lb), wherein preferablyR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent.A particularly preferred embodiment of the precursor (I, lb) is the precursor (lb’):In one embodiment of the invention, the precursor (I), preferably (la, la’) is reacted to MFA (III) via three a, p-substituted propionic acid derivative intermediates (II) before being converted to MFA (III), such three intermediates being indicated as intermediates (Ila), (lib) and (He).The a, p-substituted propionic acid derivative intermediate (Ila) is characterized through the formula (II) above, whereinR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a diazo substituent, or an amino group.Particularly preferred embodiments of intermediate (Ila) are the intermediates (Ila’) and (Ila”):The a, p-substituted propionic acid derivative intermediate (lib) is characterized through the formula (II) above, whereinR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent.A particularly preferred embodiment of intermediate (lib) is the intermediate (lib’):The a, p-substituted propionic acid derivative intermediate (He) is characterized through the formula (II) above, whereinR1is a halogen group or a pseudohalogen group, preferably a halogen group; and R2is methyl; andX is a fluoro substituent.A particularly preferred embodiment of intermediate (He) is the intermediate (He’):In another embodiment of the invention, the precursor (I), preferably (lb, lb’) is reacted to MFA (III) via one a, p-substituted propionic acid derivative intermediate (II) before being converted to MFA (HI), such intermediate being indicated as intermediate (lid) characterized throughR1is a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent.A particularly preferred embodiment of intermediate (I Id) is the intermediate (I Id’):In the sense of the invention, regarding all of the embodiments of compounds (I) and (II), the leaving group R1is selected from halogens such as chlorine, bromine or iodine, from pseudohalogens such as cyanide, cyanate or thiocyanate, or from the group of substituted or unsubstituted alkoxy- or aryloxycarbonyls.In the sense of the invention, substituted or unsubstituted alkoxy- or aryloxycarbonyl groups that can be introduced as leaving groups R1in principle comprise all substituted or unsubstituted alkoxy- or aryloxycarbonyl groups. It is preferable when said groups are substituted alkoxy- or aryloxycarbonyl groups which provide electronwithdrawing substituents in their molecular structure. Electron-withdrawing substituents commonly present in suitable substituted alkoxy- or aryloxycarbonyl groups may be (-CF3), (-CCI3), (-CBrs), (-CI3), (-NO2), a sulfonyl substituent, or combinations thereof. However, in the case of aryloxycarbonyl groups, unsubstituted species are preferred as well. Therefore, preferred substituted or unsubstituted alkoxy- or aryloxycarbonyl groups include benzoate, trifluoroacetate, trichloroacetate, tribromoacetate, triiodoacetate, benzenesulfonate, p-toluenesulfonate, m-toluenesulfonate, o-toluenesulfonate, p- chlorobenzenesulfonate, m-chlorobenzenesulfonate, o-chlorobenzenesulfonate, p-bromobenzenesulfonate, m-bromobenzenesulfonate, o-bromobenzenesulfonate, p- iodobenzenesulfonate, m-iodobenzenesulfonate, o-iodobenzenesulfonate, p- nitrobenzenesulfonate, m-nitrobenzenesulfonate, o-nitrobenzenesulfonate, methanesulfonate, ethanesulfonate, n-propanesulfonate, i-propanesulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethansulfonate or triiodomethanesulfonate. Preferred organic acid groups are trifluoroacetate and p- toluenesulfonate, especially preferred is trifluoroacetate.Preferred choices for R1regarding all intermediates (II) are chlorine, bromine, trifluoroacetate and p-toluenesulfonate, especially preferred are chlorine and trifluoroacetate.In the sense of the invention, regarding all of the embodiments of the compounds (I) and (II), a linear or branched C1-C3 alkyl when defining R2is a linear or branched C1- C3 alkyl chain selected from methyl, ethyl, n-propyl and i-propyl, preferred is methyl. The group C1-C3 alkyl also covers a group C1-C2 alkyl as well as the individual selection of a C1-, C2- or Cs-alkyl group.In the sense of the invention, regarding all of the embodiments of the compounds (I) and (II), a substituted or unsubstituted phenyl group when defining R2is bound by any possible ring carbon atom to the oxygen to which R2is bound, forming a CPhenyi-0 bond in the compounds (I) or (II).A substituted or unsubstituted phenyl group when defining R2comprises (unsubstituted) phenyl- and phenyl being substituted with 1 , 2 or 3 same or different substituents selected from Ci-Cs-alkyl as defined above as a substituent R2, or 1 , 2 or 3 same or different substituents selected from Ci-Cs-alkoxy.In the sense of the invention, a Ci-Cs-alkoxy residue as a substituent on phenyl groups when defining R2is a linear or branched Ci-Cs-alkoxy chain selected from methoxy, ethoxy, n-propyloxy and i-propyloxy. Ci-Cs-alkoxy also covers a group C1-C2- alkoxy as well as the individual selection of a C1-, C2- and Cs-alkoxy groups.Preferably substituted phenyl includes Ci-Cs-alkyl-substituted phenyl wherein phenyl is substituted with 1 , 2 or 3 same or different Ci-Cs-alkyl moieties. Examples comprise p-tolyl-, m-tolyl-, o-tolyl-, 2,3-xylyl-, 2,4-xylyl-, 2,5-xylyl-, 2,6-xylyl-, 3,4-xylyl-, 3,5-xylyl-, 1 ,2,3-trimethylphenyl-, 1 ,2,4-trimethylphenyl-, and 1 ,3,5-trimethylphenyl-. Preferred are phenyl-, p-tolyl-, m-tolyl- and o-tolyl-.Most preferred is unsubstituted phenyl.In the sense of the invention, regarding all of the embodiments of compounds (I) and (II), an amino group such as in the definition of X is selected from neutral amines such as amino (-NH2), and mono- and dialkyl-amino, wherein “alkyl” covers C1-C3 alkyl as defined above for R2. Examples comprise (-N((CH3)H)), (-N(CH3)2), (-N((CH2CH3)H)), (-N(CH2CH3)2), (-N((CH2CH2CH3)H)), (-N(CH2CH2CH3)2), (-N((C(CH3)2H)H)),(-N((C(CH3)2H))2). An amino group such as in the definition of X further comprises therespective salts of amino, mono- and dialkyl-amino as defined above, such as (-[NH3]+), (-[N((CH3)H2)]+), (-[N((CH3)2H)]+), (-[N(CH3)3]+), (-[N((CH2CH3)H2)]+),(-[N((CH2CH3)2H)]+), (-[N(CH2CH3)3]+), (-[N((CH2CH2CH3)H2)]+), (-[N((CH2CH2CH3)2H)]+), (-[N(CH2CH2CH3)3]+), (-[N((C((CH3)2H)H2)]+), (-[N((C((CH3)2H)2H)]+) or(-[N(C((CH3)2H)3]+).Preferred amino groups are selected from (-NH2), (-N(CH3)2), (-[NH3]+) and (-[N((CH3)2H)]+), especially preferred are (-NH2) and (-[NH3]+).In the sense of the invention, regarding all of the embodiments of compounds (I) and (II), a diazo substituent such as in the definition of X is an unsubstituted diazido substituent (-N2).In particularly preferred embodiments of the invention compounds (I) and (II) include precursors (la’) and (lb’) as well as intermediates (Ila’), (Ila”) (lib’), (lie’) and (lid’):II. First Embodiment of the Process of the Invention (Route I)In a first and preferred embodiment the process of the invention is carried out starting with a precursor (I), preferably precursor (la, la’), which is reacted to MFA (III) via intermediates of the formula (II) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-C3alkyl , or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.In particular, the process according to this first embodiment provides an intermediate (Ila) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a diazo substituent or an amino group.More preferably, the process according to this first embodiment provides an intermediate (Ila1) as shown above.In this particular embodiment of the invention, it is preferable that the group X of the precursor (I, la, la’) is an amino group as defined in the list of amino groups.The intermediates obtained in the specific process according to said first embodiment are defined by carrying a halogen or a pseudohalogen group at the position of R1. To provide such intermediates the reaction according to the first embodiment comprises a halogenation or a pseudohalogenation step to replace the -OH group in the precursor (I, la, la’) by a halogen or a pseudohalogen.Depending on the substituent R2in the precursor (I, la, la’) the process may further comprise a step of protecting and deprotecting the carboxyl group. In principle, all commonly used protecting reactions for carboxyl group can be applied. For example, epoxidation and de-epoxidation or esterification and de-esterification can be conducted. Preferably, an esterification and subsequent ester hydrolysis is applied to form the intermediate (II), wherein the group R2is finally a hydrogen.The esterification of the precursor serves to protect a carboxyl group -(C=O)-OH in precursors (I, la, la’) wherein R2is hydrogen during the following halogenation or pseudohalogenation of the hydroxy group in precursor (I) or preferably (la, la’). After the successful halogenation or pseudohalogenation, the ester that was formed to protect the carboxyl group -(C=O)-OH during the halogenation or pseudohalogenation step may be acidically hydrolyzed to retain the -(C=O)-OH group after the successful halogenation or pseudohalogenation. This also leads to the formation of an amino acid or an amino acid salt in the form of an intermediate (II) or preferably (Ila, Ila’, Ila”), facilitating the next reaction steps.Such esterification step can be carried out in an acidic alcohol solution. In principle, all alcohols are suitable to provide a protective ester in a carboxyl group -(C=O)-OH on a precursor (I, la, la’). However, it is preferable to provide an alcohol according to the formula R2-OH, wherein R2is either a linear or branched Ci-Cs-alkyl or a substituted or unsubstituted phenyl group as defined above.In the sense of the invention, suitable alcohols for the esterification of a precursor or preferably a precursor (la, la’) comprise methanol, ethanol, propanol, isopropanol, phenol, p-cresol, m-cresol, o-cresol, 2,3-xylenol, 2,4-xylenol, 2,5-xylenol, 2,6-xylenol, 3,4-xylenol, 3,5-xylenol, 2,3,5-trimethylphenol, 2,3,6-trimethylphenol and 2,4,6- trimethylphenol. Preferred are methanol, ethanol, propanol, isopropanol and phenol, especially preferred is methanol.In the sense of the invention, acids that can typically be applied for the acidification of the alcohol solution in the context of the esterification step include SOCh, SOBr2, SO2CI2, SO2Br2, PCI3PBr3, HCI, HBr and HF. Preferred is SOCI2.In the Next step, the precursor (I) is either halogenated or pseudohalogenated. While the halogenation is usually easier to conduct, the pseudohalogenation may offer an easier elimination of the introduced pseudohalogen, which may be desirable in certain cases. The pseudohalogenation according to the invention may be conducted by any appropriate, literature known means.The precursor (I), preferably a precursor (la, la’), which carries an ester group is next halogenated using a halogenation agent, providing intermediates carrying a halogen on the position R1. However, the ester group may also be pseudohalogenated. Preferably, a halogenation is conducted, and the conducted halogenation is a chlorination, so that preferably R1in any embodiment described herein is Cl.Halogenation agents in the sense of the present invention may in principle include all suitable phosphor halogenides. Preferred phosphor halogenides can be selected from PCI5, PBrs and PI3. Preferred is PCI5.The halogenation in the sense of the present invention is conducted in an appropriate solvent selected from the acyl halogenides. It is generally preferred to use an acyl halogenide in a complimentary manner to the chosen phosphor halogenide, e. g. if PCI5 is used, an acyl chloride should be used. Suitable acyl halogenides can preferably be selected from acetyl chloride and acetyl bromide. Preferred is acetyl chloride.In a further step according to the present invention, the halogenated precursor (I) carrying an ester group, preferably an esterified and halogenated precursor (la, la’), is hydrolyzed to form an intermediate (II), preferably an intermediate of the formula (Ila, Ila’, Ila”).Hydrolyzation can be carried out in aqueous acidic medium. In the sense of the present invention, acidic ester hydrolysis is conducted with any acid capable of producing an amino acid salt.In the sense of the invention, possible acids to produce a suitable amino acid salt comprise HCI, HBr, HI and H2SO4. Preferred is HCI.The intermediate (II), preferably the intermediate (Ila, Ila’, Ila’), is then treated with a nucleophilic fluorinating agent to replace the amino group on the position X against a fluorine group.In the sense of the invention, a nucleophilic fluorinating agent may be selected from the group of anhydrous HF, KF, KHSO4 • 13HF, CsF, diethylaminosulfur trifluoride (DAST), complexes with HF and a solvent such as Olah’s reagent (pyridine-HF), or such as with trimethylamine-, triethylamine-, substituted pyridine-, and triethanolaminepoly (hydrogen fluoride), or, dimethylpropylene urea hydrogenfluoride (DMPU-HF), IF5- pyrridine-HF, and other nucleophilic fluorination agents such as morpholinosulfur trifluoride, perfluoro-1-butanesulfonyl fluoride, pyridine-2-sulfonyl fluoride, pyrimidine-2- sulfonyl fluoride, tetrabutylammonium difluorotriphenylsillicate, tetrabutylammonium difluorotriphenylstannate 4-tert-Butyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEAD™), PhenoFluor™, AlkylFluor™, 2-fluoro-1-methylpyridinium p- toluenesulfonate, Ishikawa’s Reagent (N,N-diethyl-(1 ,1 ,2,3,3,3-hexafluoropropyl)amine + N,N-diethyl-l-pentafluoropropylamine), amine-poly(hydrogenfluoride), and mixtures thereof.In principle, all nucleophilic fluorination agents can be applied whether they are in a solid or in a liquid form. Examples of solid nucleophilic fluorinating agents include commercially available fluorinating sources such as DAST, XtalFluor-M® or-E®, KF, CsF, and Bu4N*F, FLUOLEAD™ or mixtures thereof. Examples of liquid nucleophilic fluorinating agents, which are preferred, include anhydrous HF (AHF), Hf-NEt3, KHSO4.13HF, HBF4,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU-HF) and Olah’s reagent and mixtures thereof.When choosing a nucleophilic fluorinating agent according to the invention, it is preferable to operate with a nucleophilic fluorinating agent that offers the least risk for the working professionals. For example, it is more preferable to use FLUOLEAD™ compared to DAST, which has explosive properties.In practice it has shown that liquid nucleophilic fluorinating agents are generally preferrable over solid nucleophilic fluorinating agents due to price advantage Solid reagents are handled as a safe alternative in lab and small scale batches but are mostly not competitive in price if high amounts are needed during manufacturing. If liquid fluorinating agents are chosen, they can serve as the solvent for the fluorination reaction, which reduces wastes. The use of anhydrous HF would serve as the best choice forfluorination steps. However, anhydrous HF is a dangerous gas and difficult to handle. It is most preferred to use Olah’s reagent as a fluorinating agent according to the invention.Olah’s reagent is a mixture of HF in an organic solvent which is capable of forming weak intermolecular interactions with the HF thus leading to the latter being stabilized in the liquid form and therefore becoming less dangerous. The organic solvent used in Olah’s reagent is pyridine.If a liquid fluorination agent is chosen, the fluorination is simply carried out in the respective fluorination agent. This method is preferred, as it is simpler to conduct and saves additional solvents.If a solid fluorination agent is chosen, the fluorination is carried out in a polar aprotic solvent. Suitable polar aprotic solvents in cases where a solid fluorination agent is chosen include halogenated solvents such as dichloromethane (DCM), 1 ,2- Dichloroethane (DCE), nitriles such as CH3CN, sulfoxides such as dimethyl sulfoxide (DMSO), amides such as dimethyl formamide (DMF), or toluene.In the sense of the invention, a diazotization step must be carried out priorly or simultaneously to the fluorination. Carrying out such a diazotization enables the nucleophilic substitution with the nucleophilic fluorinating agent. Conducting a diazotization step priorly or simultaneously to the fluorination step thus increases the conversion rate and the yield of the targeted fluorinated intermediate (lib, lib’).In the sense of the present invention, possible diazotizing agents comprise HNO2, UNO2, NaNC>2, KNO2, Ca(NC>2)2, tert-butyl nitrite, and mixtures thereof. Preferred areHNO2, NaNCh, tert-butyl nitrite, and mixtures thereof, especially preferred is tert-butyl nitrite.In practice it has shown, that applying a liquid diazotizing agent such as tert-butyl nitrite is advantageous. Application of liquid diazotizing agents enables working at higher temperatures compared to solid ones, which reduces the necessary energy cost to conduct the reaction according to the invention. Additionally, liquid diazotizing agents can more easily be applied to flow chemistry as fluorination reactions can be very exothermic reactions.The preferable liquid diazotization agent tert butyl nitrite can be applied without needing an additional drying or purification step and lead to the desired diazotized intermediates.If the fluorination in the sense of the present invention using a fluorination agent is carried out using Olah’s reagent, the ratio of pyridine to HF may comprise 25:75 to 75:25, preferred embodiments include 25:75, 30:70, 35:65, 40:60, 45:55 and 50:50, especially preferred is 30:70.In the sense of the invention, if a diazotization step is carried out additionally to the fluorination step the reaction is preferably conducted at low temperatures, comprising -20 °C to 20 °C. Preferably, if a solid diazotization agent such as NaNCh is used in conjunction with Olah’s reagent, temperatures of -20 °C, -19 °C, -18 °C, -17 °C, -16 °C, -15 °C, -14 °C, -13 °C, -12 °C, -11 °C or -10 °C are used. In such a case, -15 °C is especially preferred.However, if in another preferred embodiment of the present invention, which involves the intermediate (Ila”), liquid diazotization agents such as tert-butyl nitrite are used together with Olah’s reagent and temperatures of -10 °C, -9 °C, -8 °C, -7 °C, -6 °C, -5 °C, -4 °C, -3 °C, -2 °C, -1 °C or 0 °C are preferable. In such a case, -5 °C is especially preferred.In the sense of the invention, the fluorination step, and also the optionally simultaneously conducted diazotization step, is conducted for 12 h to 24 h. Preferably, it is conducted for 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h or 22 h, most preferably it is conducted for 18 h.Subsequent to the fluorination step the intermediate (lib), preferably the intermediate (lib’), is preferably subjected to an aqueous work up. An aqueous work-up in the sense of the present invention may be in the presence of an additional anhydrous fluoride source. The presence of an additional anhydrous fluoride source during the aqueous work-up has the advantage to remove HF extracted into the organic phase. It increases also the nucleophilic fluoride source. Suitable anhydrous fluoride sources for the aqueous workup comprise anhydrous alkali fluorides such as anhydrous LiF, anhydrous NaF, anhydrous KF, anhydrous RbF, or anhydrous CsF.The resulting intermediate (lib), preferably in the form of the intermediate (lib’), may be acidically esterified to yield an intermediate (He), preferably in the form of the intermediate (lie’).Such acidic esterification of the intermediate (lib), preferably in the form of the intermediate (lib’), is preferably conducted in the same way previously described herein in regard to acidic esterifications.MFA can then be obtained by conducting an elimination reaction which removes the halogen from the intermediate (He, lie’), thus forming the terminal double bond characteristic for MFA. In principle, the halogen can be removed by any suitable procedure comprising heating in a basic, polymerization inhibiting environment, catalytic elimination, or reactive distillation, preferably the elimination is conducted by reactive distillation.It is advantageous to perform a reactive distillation, because such a procedure simultaneously removes the halogen and furthermore removes the reaction product, MFA, from the reaction mixture. This saves time and resources, as both steps can be conducted in the same setup.For example, an intermediate (He, He’) can be reactively distilled in a suitable, solvent in the presence of a polymerization inhibitor as well as a weak base to form the product MFA (HI).MFAIn the context of this invention, the reactive distillation can be conducted in any solvent an intermediate (lie, He’). Suitable solvents can be selected from / V-methyl-2- pyrrolidone (NMP), Dimethyl Sulfoxide (DMSO), Dimethylacetamide (DMA), Aniline, Nitrobenzene, Phenol or ethylene glycol. Preferred are NMP, DMSO or DMA, especially preferred is NMP.In the context of the invention, the reactive distillation can be conducted in the presence of any suitable polymerization inhibitor. Examples for polymerization inhibitorscomprise 4-tert-butylcatechol (TBC), 2,6-di-tert-butyl-4-methylphenol (BHT), mequinol or hydroquinone. Preferred are TBC or BHT, especially preferred is BHT.In the context of the invention, any suitable base can be used for the reactive distillation. Suitable bases in the sense of the invention may comprise alkali metal derived bases. Suitable alkali metal derived bases can be selected from U3PO4, Na3PC>4, K3PO4, U2CO3, Na2CO3, K2CO3, LiHCO3, NaHCO3or KHCO3. Preferred are Na3PO4, K3PO4, Na2CO3and K2CC>3, especially preferred is NasPCIn the context of the invention, the reactive distillation is ideally conducted between 145 °C and 160 °C, preferably at 148 °C, 149 °C, 150 °C, 151 °C, 152 °C, 153 °C or 154 °C, most preferably at 150 °C.The method allows to prepare MFA.An advantage of the process according to the invention is that intermediate (lib, lib’) can be further reacted without the necessity of a purification at this step. The crude yield after the fluorination and aqueous work-up can thus quickly be reacted further, which saves time and purification agents.Moreover, this method offers the advantage that it does not expose working professionals to toxic MFA precursors. Rather than that, the reaction can be started from a-amino acid derivatives. Furthermore, the reaction of the intermediate (Ila) to an intermediate (He) via an intermediate (lib) can be conducted without the isolation of the intermediate (lib) or (lib’). This not only reduces contact of working professionals to the reactants but also decreases chemical wastes in the form of e. g. washing or purification solvents. Furthermore, setup effort for the reaction steps according to the invention is decreased, which further enables easier development of automated reaction procedures. This is also favoured if the preferable process of reactive distillation is conducted to synthesize MFA from precursor (He).A particularly preferred Route I is illustrated by the following reaction scheme:The alternative, preferred, intermediate route wherein tert-butyl nitrite is used as the diazotization agent is illustrated in the following reaction scheme:III. Second Embodiment of the Process of the Invention (Route II)For another embodiment of the process described herein, a precursor of the general formula (lb), preferably in the form of precursor (lb’), is used.The precursor (lb), preferably in the form of precursor (lb’), is reacted with an organic acid anhydride (IV) to receive an intermediate of the formula (lid), preferably (lid’). In the context of this embodiment of the present invention, an organic acid anhydride can be any organic acid anhydride according to the formula (IV):whereinR3and R3’ are either different or the same and selected from the list of organic leaving groups, comprising electron-withdrawing substituents in their molecular structure.Electron-withdrawing substituents commonly present in suitable organic leaving groups may include (-CF3), (-CCI3), (-CBrs), (-CI3), (-NO2), sulfonyl groups or combinations thereof. However, if the leaving groups include an aromatic ring, no further substituents are absolutely necessary. Therefore, preferred organic leaving groups include benzyl, trifluoroacetyl, trichloroacetyl, tri bromoacetyl, triiodoacetyl, benzenesulfonyl, p- toluenesulfonyl, m-toluenesulfonyl, o-toluenesulfonyl, p-chlorobenzenesulfonyl, m- chlorobenzenesulfonyl, o-chlorobenzenesulfonyl, p-bromobenzenesulfonyl, m bromobenzenesulfonyl, o-bromobenzenesulfonyl, p-iodobenzenesulfonyl, m iodobenzenesulfonyl, o-iodobenzenesulfonyl, p-nitrobenzenesulfonyl, m nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, methanesulfonyl, ethanesulfonyl, n- propanesulfonyl, i-propanesulfonyl, trifluoromethanesulfonyl, trichloromethanesulfonyl, tribromomethansulfonyl or triiodomethanesulfonyl. Preferred organic leaving groups are trifluoroacetyl and p-toluenesulfonyl, especially preferred is trifluoroacetyl.Preferably, the organic anhydride is trifluoro acetic acid (TFAA):The reaction of a precursor (lb), preferably a precursor (lb’) and an organic anhydride (IV) to an intermediate (lid), preferably an intermediate (lid’), can advantageously be conducted at low reaction temperatures and during short durations.In the sense of the invention, low reaction temperatures regarding the reaction between compound (lb), preferably in the form of (lb’), and compound (IV) refer to temperatures in a range of 15 °C to 30 °C, preferably at 17 °C, 18 °C, 19 °C, 20 °C, 21 °C, 22 °C or 23 °C, most preferably at 20 °C.In the sense of the invention, the reaction of (lb), preferably in the form of (lb’) and (IV) is carried out at short durations, preferably in a time range of 1 h to 6 h, more preferably for 3 h, 3.5 h, 4 h, 4.5 h or 5 h. Especially preferred are 4 h.Thus, the production of a precursor (lid) can be conducted in a resourceful manner. In comparison to processes disclosed in the state of the art, the intermediate (lid) if produced according to the invention, requires no heating and can be prepared in less than 7 hours. This reduces energy costs in a remarkable way compared to previously conducted methods.The reaction according to the invention of precursor (lb), preferably (lb’) and (IV) is preferably carried out in an aprotic organic solvent. In principle, any aprotic solvent is possible, as the reaction mixture does not have to be heated, low boiling points do not exclude possible solvents from scope of aprotic solvents suitable for the process according to the invention. Examples of suitable aprotic solvents comprise dichloromethane (DCM), trichloromethane, tetrachloromethane, dichloroethane, tetrahydrofuran, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), preferred is DCM.In the sense of the invention, the intermediate (lid), preferably (lid’), resulting from the reaction of (lb), preferably (lb’), and (IV) can be further reacted to yield MFA without any isolation or purification of (lid) or (lid’). This means that the crude yield of intermediate (lid) can quickly be further reacted to MFA, saving time and resources.In principle, any elimination process, such as the ones listed above, to remove the organic acid residue formed in (lid) on position C3 of the propanoate structure is suitable. However, the introduction of the organic leaving groups according to the invention enable a mild elimination of said groups to yield MFA.An elimination in the sense of the invention means an elimination process which requires less heat, less time or no application of a vacuum, compared to usually conducted elimination processes of comparable syntheses.Possible elimination processes may comprise slight heating in a basic, polymerization inhibiting environment, catalytic elimination, or a reactive distillation of an intermediate (lid).Preferably, elimination reactions are conducted to produce MFA from precursor (lid). Compared to the elimination processes known from the literature, the elimination of the organic leaving group of compound (lid) can be conducted at low temperatures and during short durations.For example, the elimination reaction according to the invention as a method to yield MFA from intermediate (lid) can be conducted at low temperatures of 35 °C to 70 °C, preferably at 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 56 °C, 57 °C, 58 °C, 59 °C, 60 °C, 61 °C, 62 °C, 63 °C, 64 °C, 65 °C, most preferred at 60 °C.Furthermore, the inventive elimination reaction can be carried out in short reaction durations in a range of 15 min to 45 min, preferably in 20 min, 22 min, 24 min, 26 min, 28 min, 30 min, 32 min, 34 min, 36 min, 38 min or 40 min most preferred in 30 min.Regarding the further reaction conditions, the elimination of the present invention may be carried out in the same solvents using the same polymerization inhibitors as described above for the reactive distillation or other possible elimination steps.The elimination reaction can be conducted using a suitable solvent selected from the list of solvents for the reactive distillation provided above. However, due to the possibility to conduct the elimination at such low temperatures, the solvents may also be selected from suitable polar aprotic solvents for the diazotization step provided above. Preferably, the reaction may be conducted in Dichloromethane (DCM).The elimination reaction can be conducted in the presence of a polymerization inhibitor selected from the list of polymerization inhibitors provided above.The elimination reaction can be conducted in the presence of a suitable base selected from the list of bases suitable for the reactive distillation provided above.The method according to the invention allows to prepare MFA.The provided method offers a very resourceful approach in the production of MFA, facilitating each key step. Temperatures above room temperature are only necessary for the reactive distillation and even there the needed temperature is decreased to less than half of what is disclosed in the prior art. Furthermore, the inventive process enables the reactive distillation to be conducted in less than an hour. Therefore, the present invention provides a method to obtain MFA in excellent purities in a much more quick and cost effective manner compared to the prior art.A particularly preferred Route II is illustrated by the following reaction scheme:IV. Preparation of Patiromer Calcium SorbitexMFA obtained by the process described herein constitutes a major component and structural unit of Patiromer Calcium Sorbitex, which is produced by processing the Methyl 2-fluoro acrylate (III) with a crosslinker in a crosslinking polymerization reaction, the obtained crosslinked polymer is subsequently deprotected, contacted with a calcium salt, as well as swelled and contacted with sorbitol to give Patiromer Calcium Sorbitex.MFA Common Crosslinkers Patiromer Monomer UnitThe following reaction scheme schematically illustrates the synthesis of thePatiromer polymer:In the sense of the invention, crosslinkers suitable for the crosslinking reaction of MFA (III) can be selected from the list of divyinyl crosslinkers such as p-divinylbenzene, m-divinylbenzene, or 1 ,7-octadiene and combinations thereof.Because 2-fluoroacrylic acid is very reactive at higher concentration, a greater amount of the polymerization reaction is observed even in the presence of butylated hydroxytoluene (BHT). A lower concentration of 2-fluoroacrylic acid is helpful to reducethe side reactions and the overall large volume is not feasible for large scale synthesis. A suitable concentration range is between about 1 M and about 2 M.In the context of the invention, a polymerization initiator is used to start the crosslinking polymerization process between MFA (III) and the crosslinkers, preferably a mixture of divinylbenzene and 1 ,7-octadiene. The polymerization initiator can in principle be any suitable polymerization initiator. Preferably, the polymerization initiator are for instance, initiators that generate polymer imitating radicals upon exposure to heat include peroxides, persulfates or azo type initiators (e.g., 2,2'-azobis(2- methylpropionitrile), lauroyl peroxide (LPO), tert-butyl hydro peroxide, dimethyl-2,2'- azobis(2-methylpropionate), 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide), 2,2'-azobis(2-(2-imidazolin-2-yl)propane), (2,2"-azo bis(2,4-dimethylvaleronitrile), azobisisobutyronitrile (AIBN) or a combination thereof. . Preferred are benzoyl peroxide and lauroyl peroxide, especially preferred is lauroyl peroxide.In the sense of the invention, a crosslinked polymer means the product of the crosslinking polymerization between MFA (III) and one or more crosslinkers to receive an alkyl polymer, preferably alkyl(2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene.Alkyl-protected Patiromer Monomer UnitThe thusly prepared crosslinked polymer, preferably the alkyl(2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene crosslinked polymer, needs to be deprotected by hydrolyzation in a further step to obtain a deprotected crosslinked polymer.Deprotected Patiromer Monomer UnitIn the context of the invention, a deprotected crosslinked polymer is the product of the inventive deprotecting hydrolyzation reaction conducted on a crosslinked polymer, preferably a (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene deprotected crosslinked polymer.In the sense of the invention, the deprotecting hydrolyzation of the crosslinked polymer can be conducted with a suitable base from the list of bases for the deprotecting hydrolization comprising NaOH, KOH, RbOH or CeOH, preferably NaOH is used.If the preferred deprotecting hydrolyzation of the crosslinked polymer is conducted, the deprotected crosslinked polymer (sodium 2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer is obtained.Sodium Patiromer Monomer UnitThe thusly prepared deprotected, crosslinked polymer, preferably (sodium 2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene, needs to be contacted with a calcium salt to obtain a cation exchange polymer.In the context of the invention, a cation exchange polymer means a deprotected, crosslinked polymer that was brought into contact with a calcium salt via slurrying.In the sense of the invention, the calcium salt can be selected from the group of CaCh, CaBr2 or Cal2 or combinations thereof.In the context of the invention, slurrying means to stir the deprotected, crosslinked polymer and the calcium salt in a solvent in which they both are non-well-soluble, so that no complete dissolution of the solutes occurs and the mixture is stirred in a slurry.The process further includes swelling the crosslinked cation exchange polymer (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene by slurrying the polymer in a solution comprising sorbitol, preferably an aqueous sorbitol solution.The crosslinked cation exchange polymer (e.g., patiromer calcium sorbitex) can be synthesized by preparing an organic phase and an aqueous phase. The organic phase typically contains a polymerization initiator, MFA of formula (III), 1 ,7-octadiene, and divinyl benzene. The aqueous phase generally contains a polymerization suspension stabilizer, a water-soluble salt, water, and optionally a buffer. The organic phase and the aqueous phase are then 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, allowed to rise up 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 alcohol / water mixtures.As described above, polymerization suspension stabilizers, such as polyvinyl alcohol, are used to prevent coalescence of particles during the polymerization process. Further, it has been observed that the addition of sodium chloride in the aqueous phase decreases coalescence and particle aggregation. Other suitable salts for this purpose include salts that are soluble in the aqueous phase. Water soluble salts can be added ata concentration of from about 0.1 wt.% to about 10 wt.%, particularly from about 2 wt.% to about 5 wt.%, and even more particularly from about 3 wt.% to about 4 wt.%.Preferably, an organic phase of MFA (III) (90 wt.%), 1 ,7-octadiene (5 wt.%) and divinylbenzene (5 wt.%) is prepared and 0.5 wt.% of lauroyl peroxide is added to initiate the polymerization reaction. Additionally, an aqueous phase of water, polyvinyl alcohol, phosphates, sodium chloride, and sodium nitrite is prepared. Under nitrogen and while keeping the temperature below about 30°C, the aqueous and organic phases are mixed together. Once mixed completely, the reaction mixture is gradually heated with continuous stirring. After the polymerization reaction is initiated, the temperature of the reaction mixture is allowed to rise up to about 95°C. Once the polymerization reaction is complete, the reaction mixture is cooled to room temperature and the aqueous phase is removed. The solid can be isolated by filtration once water is added to the mixture. The filtered solid is washed with water and then with a methanol / water mixture. The resulting product is a crosslinked (methyl 2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene terpolymer.As discussed herein, after polymerization, the product may be hydrolyzed or otherwise deprotected by methods known in the art. For hydrolysis of the polymer having ester groups to form a polymer 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 the alkyl (e.g., methyl) group and form the carboxylate salt. Alternatively, the polymer can be hydrolyzed with a strong acid (e.g., hydrochloric acid) to form the carboxylate salt. Preferably, the (methyl 2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene terpolymer is hydrolyzed with an excess of aqueous sodium hydroxide solution at a temperature from about 30°C to about 100°C to yield (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 an alcohol.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 for another cation by contacting the sodium salt with an excess of an aqueous metal salt to yield an insoluble solid of the desired polymer salt. After the desired ion exchange, the product is washed with an alcohol and / or water and dried directly or dried after a dewatering treatment with denatured alcohol; preferably, the product is washed with water and dried directly. For example, the sodium salt of the cation exchange polymer is converted to the calcium salt by washing with a solution that substitutes calcium for sodium, for example, by using calcium chloride, calcium acetate, calcium lactate gluconate, or a combination thereof. And, more specifically, to exchange sodium ions for calcium ions, the (sodium 2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene terpolymer is contacted with an excess of aqueous calcium chloride to yieldan insoluble solid of crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene terpolymer.Using this suspension polymerization process, cross-linked polyMeFA polymer is isolated in good yield, generally above about 85%, more specifically above about 90%, and even more specifically above about 93%. The yield of the second step (i.e., hydrolysis) preferably occurs in 100%, providing an overall yield above about 85%, more specifically above about 90%, and even more specifically above about 93%.To add sorbitol to the sorbitol stabilized compositions, the salt of the polymer is swelled and contacted with a solution of sorbitol (e.g. slurried with an aqueous solution of sorbitol), typically with the slurry containing an excess amount of sorbitol based on polymer weight. The slurry is maintained for at least 3 hours and ambient temperature and pressure. The solids are then filtered off and dried to desired moisture content.The terms “about” and “around” are to signify that the respective exact value is designated, or that the approximate value is designated. Thus, for example, “at least about 1 ,000” shall, be interpreted to mean “at least 1 ,000” and, be interpreted to mean “at least approximately 1 ,000.”1. EXAMPLESRoute I a. Measurement parameters and general informationThe following GC-MS Analysis parameters were used:GC Instrument: Agilent 7890B; Solvent: dichloromethane; Column: Agilent 190915-433 HP-5ms; Pressure 20 kPa; Inlet Temperature: 250 °C; Injection volume: 1.0 pL; Split 23 GC / MS: Agilent 5977B MSD; Ion Source: El ;Source Temperature: 230 °C; Quad Temperature: 150 °C; Fixed Electron Energy: 70 eV; and Scan time segments: time 0.5, start mass 40, end mass 550.The1H- and13C N MR- spectra have been measured by a Magnet System 400 MHz Ultra shield plus NMR by Bruker BioSpin. The chemical shift is referred in in parts per million (ppm) and in reference to tetramethyl silane.The present example 1 has been carried out following the process according to the following reaction scheme:b. Reaction of Precursor (la’) to intermediate (Ila’)The reaction was performed according to literature (Walter, T., Collenburg, L., Japtok, L., Kleuser, B., Schneider-Schaulies, S., Muller, N., Becam, J., Schubert-Unkmeir, A., Kong, J. N., Bieberich, E., & Seibel, J. (2016). Incorporation and visualization of azidofunctionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells. Chemical Communications, 52(55), 8612-8614. https: / / doi.org / 10.1039 / C6CC02879A). A solution of L-serine (la’) (55.9 g, 532 mmol, 1.00 eq.) in anhydrous methanol (600 mL) was cooled to 0 °C. To the resulting solution thionyl chloride (46.4 mL, 76.0 g, 639 mmol, 1.20 eq.) was added dropwise and the solution was stirred at 0 °C. The resulting suspension was stirred at 0 °C for 1 h before it was allowed to warm to room temperature while stirring for another 1 d. The solvent was removed by distillation and the residue was washed with ethyl acetate (3 x 50 mL). The title compound L-Serine methyl ester was obtained as a white crystalline solid.The reaction was performed according to literature (Walter, T., Collenburg, L., Japtok, L., Kleuser, B., Schneider-Schaulies, S., Muller, N., Becam, J., Schubert-Unkmeir, A., Kong, J. N., Bieberich, E., & Seibel, J. (2016). Incorporation and visualization of azidofunctionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells. Chemical Communications, 52(55), 8612-8614. https: / / doi.org / 10.1039 / C6CC02879A). A suspension of L-Serine methyl ester (19.9 g, 128 mmol, 1.00 eq.) in acetyl chloride (200 mL) was cooled to 0 °C. Afterwards PCIs (32.0 g, 154 mmol, 1.20 eq.) was added in small portions. The resulting suspension was stirred at 0 °C for 3 h before it was allowed to warm to room temperature while stirring for another 3 d. The reaction mixture was cooled to 0 °C for 1 hour to crystallize the product. The obtained white crystals were filtered and washed with ethyl acetate (2 x 50 mL). After drying in vacuum, the L-Chloroalanine methyl ester was obtained as a white solid.L-Chloroalanine methyl ester (23.2 g, 128 mmol, 1.00 eq.) was dissolved in HCI (100 mL, 37% w / w) and H2O (100 mL). The resulting mixture was refluxed for 6 h. The solvent was removed by distillation under reduced pressure (5 mbar). After drying in vacuum, the L-chloroalanine salt (Ila’) title compound was obtained as a white crystalline solid.1H NMR (400 MHz, DMSO-cfe) 6 = 8.86 (s, 3H), 4.56 - 4.42 (m, 1 H), 4.22 - 4.04 (m, 2H) c. Reaction of intermediate (Ila’) via intermediate (lib’) to intermediate (He’)Solid Sodium nitrite as diazotization agent:Sodium nitrite NaNC>2 (11.6 g, 168 mmol, 1.50 eq.) was dried in vacuum (4 mBar) at 140 °C for 2 h. In a separate flask, L-chloroalanine salt (Ila’) (17.9 g, 112 mmol, 1.00 eq.) was dissolved in poly(hydrogen fluoride) (Olahs reagent, 200 mL, HF 70% : Pyridine 30%, w:w ) under nitrogen atmosphere and the solution was cooled to -20 °C. Olah’s reagent acted as solvent and fluoride source. The freshly dried NaNO2 was added in smallportions within 1 h. The solution was further stirred at -15 °C for 2 h until it was allowed to warm to rt. Anhydrous KF (45.5 g, 784 mmol, 7.0 eq.) was added to the reaction mixture to quench excess HF and to higher the fluoride source. The resulting suspension was stirred for 16 h. The reaction mixture was poured into water and the aqueous reaction mixture was extracted with ethyl acetate (8 x 200 mL). The organics extracts were washed with aqueous saturated sodium chloride solution (1 x 500 mL) and were dried over Magnesium sulfate. The solvent was removed under reduced pressure and the solvent of the crude intermediate (lib’) was exchanged to anhydrous methanol. Surprisingly, no further purification was needed.1H NMR (400 MHz, DMSO-cfe) 6 = 5.49 - 5.27 (m, 1 H), 4.16 - 3.89 (m, 2H).19F NMR (376 MHz, DMSO-cfe) 6 = -192.80 - -194.12 (m).Liquid tert-butyl nitrite as diazotization agent:The 3-Chloro-L-alanine (Ila”) (8.5 g, 96 mmol, 1.00 eq.) was dissolved in poly(hydrogen fluoride) (Olahs reagent, 59.79 mL, HF 70% : Pyridine 30%, w:w) under nitrogen atmosphere. After stirring of the 3-Chloro-L-Alanin (Ila’) solution at -5 to 0°C for 30 min tert-butyl nitrite (18.93 mL, 145 mmol, 1.50 eq.) was added dropwise over 15 min and the solution was further stirred at -5 to 0 °C. Olah’s reagent acted as solvent and fluoride source. The solution was allowed to warm to room temperature over 2.5 h and was stirred at room temperature overnight. The reaction mixture was poured into ice water and was extracted with dichloromethane (3 x 130 mL). Anhydrous potassium fluoride KF (60 g, 1032 mmol, 10.7 eq.) was added to the reaction mixture to quench excess HF and to higher the fluoride source. The resulting suspension was stirred for 2.5 h and the aqueous reaction mixture was extracted with ethyl acetate (3 x 130 mL). The solvent mixture was removed under reduced pressure and the solvent of the crude intermediate (lib’) was exchanged to anhydrous methanol. Surprisingly, no pre-drying of the diazotization agent was required and no further purification was needed.The addition of a liquid diazotization agent compared to a solid sodium salt helps to convert this reaction into flow chemistry. Also, no pre-drying of the diazotization agent is required which will decrease cycle time during production.A solution of intermediate (lib’, (R)-3-chloro-2-fluoropropanoic acid (crude reaction mixture, 1.00 eq.) in anhydrous methanol (250 mL) was cooled to 0 °C. To the resulting solution thionyl chloride (8.50 mL, 13.9 g, 117 mmol, 1.20 eq) was added dropwise and the resulting solution was stirred at 0 °C for 1 h before it was allowed to warm to room temperature while stirring for 2 d. The solvent was removed under reduced pressure. The reaction mixture was diluted with water (500 mL) and the mixture was extracted with dichloromethane (3 x 100 mL). The organic extracts were dried over Magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The intermediate (He’) may or may not be isolated as a yellow oil. Surprisingly, no purification was needed at this step. The final purification will be performed during reactive distillation.1H NMR (400 MHz, DMSO-cfe) 5 = 5.71 - 5.47 (m, 1 H), 4.23 - 3.92 (m, 2H), 3.77 (s, 3H).19F NMR (376 MHz, DMSO-cfe) 5 = -194.30 - -195.27 (m).Retention times in GC / MS Analysis: Intermediate (lib’) = 14.404 min.MS (GC / MS, 70 eV, El) m / z [fragment]: 108.9 [C3H3CIFO+], 81.0 [C2H3CIF+], 59.0 [C2H3O2+], 46.0 [C3H5FO22+], d. Reaction of intermediate (He’) to MFA (III)To a solution of BHT (8.30 g, 47.1 mmol, 0.8 eq.) in N-methyl-2-pyrrolidone NMP (50 mL, ACS reagent 99%) in a three-neck flask tripotassium phosphate K3PO4 (23.0 g, 108 mmol, 2.3 eq.) was added. The pressure of the distillation apparatus was reduced to 150 mbar and the three-neck flask was heated to 150 °C. The receiving flask (which contained a small amount BHT) was cooled to -78 °C. Afterwards Intermediate (He’) (R)- 3-chloro-2-fluoropropanoate (6.62 g, 47.1 mmol, 1.0 eq.) was added in small portions (0.5 mL) to the three-neck flask. The title compound MFA (III) was directly purified via distillation and was obtained as a colorless liquid.1H NMR (400 MHz, DMSO-cfe) 6 = 5.74 (dd, J = 45.7, 3.8 Hz, 1 H), 5.59 (dd, J = 14.3, 3.8 Hz, 1 H), 3.79 (s, 3H).19F NMR (376 MHz, DMSO-cfe) 5 = -117.00 - -117.86 (m).Retention times in GC / MS Analysis: Methyl 2-fluoroacrylate = 3.243 min.MS (GC / MS, 70 eV, El) m / z [fragment]: 104.0 [C4H5FO2+], 86.0 [C4H6O2+], 73.0 [C3H2FO+], 59.0 [C2H3O2+], 45.1 [C3H5FO22+],2. Example - Preparation Route II a. General informationThe present example has been carried out following the process according to the following reaction scheme (without usage of reactive distillation)b. Reaction of Precursor (lb’) to intermediate (lid)To a solution of methyl (S)-2-fluoro-3-hydroxypropanoate (lb’) (498 mg, 4.08 mmol, 1.00 eq.) in anhydrous dichloromethane (anhydrous, 25 mL) trifluoroacetic anhydride (TFAA, 2.44 mL, 3.68 g, 17.5 mmol, 4.30 eq.) was added dropwise over 10 min. The resulting solution was stirred at rt for 4 d and was stopped by the addition of aqueous sat. sodiumhydrogen carbonate NaHCOs (200 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic phase was washed with aqueous saturated sodium chloride solution (1 x 200 mL) and were dried over Magnesium sulfate. The solvent was removed under reduced pressure and the title compound (lid) was obtained as a colorless oil.1H NMR (400 MHz, CDCI3) 6 = 5.34 - 5.11 (m, 1 H, 2-CH), 4.88 - 4.60 (m, 2H, 3-CH2), 3.84 (s, 3H, 5-CH3).19F NMR (376 MHz, CDCI3) 6 = -75.01 , -197.52 - -198.44 (m).Retention times in GC / MS Analysis: intermediate (lid) methyl (S)-2-fluoro-3-(2,2,2- trifluoroacetoxy)propanoate = 16.321 min.MS (GC / MS, 70 eV, El) m / z [fragment]: 187.0 [C5H3F4O3+], 159.0 [C4H3F4O2+], 150.9 [C5H7FO4+], 97.0 [C2F3O+], 59.0 [C2H3O2+]. c. Reaction of intermediate (lid’) to MFATo a solution of (S)-2-fluoro-3-(2,2,2-trifluoroacetoxy)propanoate precursor (lid) (315 mg, 2.24 mmol, 1.0 eq.) and BHT (395 mg, 1.79 mmol, 0.8 eq.) in N-methyl-2-pyrrolidone NMP (20 mL, ACS reagent 99%) tripotassium phosphate K3PO4(2.85 g, 13.4 mmol, 6.0 eq.) was added. The resulting suspension was heated to a much lower temperature of 60 °C for 30 min before it was allowed to cool to room temperature. Surprisingly, MFA was isolated through such mild reaction conditions without high vacuum. After filtration, the product was detected via GC-MS and compared to a reference GC-MS of MFA. No reactive distillation was conducted and needed.Retention times in GC / MS Analysis: methyl 2-fluoroacrylate = 3.265 min.MS (GC / MS, 70 eV, El) m / z [fragment]: 104.0 [C4H5FO2+], 85.9 [C4H6O2+], 73.0 [C3H2FO+], 59.0 [C2H3O2+], 45.0 [C3H5FO22+].3. Example - Preparation of Patiromer Sorbitex from MFAMethyl 2-fluoroacrylate (MFA) is prepared as above in Example 1. Divinylbenzene (DVB) is purchased from Aldrich, technical grade, 80%, mixture of isomers, and is used as received. 1 ,7-octadiene (ODE), lauroyl peroxide (LPO), polyvinyl alcohol (PVA) (typical molecular weight 85,000-146,000, 87-89% hydrolyzed), sodium chloride (NaCI), sodium phosphate dibasic heptahydrate (Na2HPO4 7H2O) and sodium phosphate monobasic monohydrate (NaH2PO4 H2O) are purchased from commercial sources and used as received.In an appropriately sized reactor with appropriate stirring and other equipment, a 90:5:5 weight ratio mixture of organic phase of monomers is prepared by mixing methyl 2- fluoroacrylate, 1 ,7-octadiene, and divinylbenzene. One-half part of lauroyl peroxide is added as an initiator of the polymerization reaction. A stabilizing aqueous phase isprepared from water, polyvinyl alcohol, phosphates, sodium chloride, and sodium nitrite. The aqueous and monomer phases are mixed together under nitrogen at atmospheric pressure, while maintaining the temperature below 30°C. The reaction mixture is gradually heated while stirring continuously. Once the polymerization reaction has started, the temperature of the reaction mixture is allowed to rise to a maximum of 95°C.After completion of the polymerization reaction, 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 yield 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 of aqueous sodium hydroxide solution at 90 °C for 24 hours to yield 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 at room temperature to an excess of aqueous calcium chloride solution to yield insoluble cross-linked (calcium 2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene copolymer.After the calcium ion exchange, the wet polymer is slurried with 25-30 % w / w aqueous solution of sorbitol at ambient temperature to yield sorbitol-loaded polymer. Excess sorbitol is removed by filtration. The resulting polymer is dried at 20-30 °C until the desired moisture content (10-25 w / w / %) is reached. This provided a solid patiromer calcium sorbitex (i.e., sorbitol-loaded, crosslinked (calcium 2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene copolymer).When introducing elements of the present invention or the preferred embodiments thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.As various changes could be made in the above compositions and process without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

Claims[1] A process for preparing methyl 2-flouro acrylate (III) comprising a reaction of a precursor of the general formula (I), to provide an intermediate of the general formula (II):(I) (II) (III) whereinR1is a leaving group comprising a halogen group, a pseudohalogen group, or a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.[2] The process according to claim 1, wherein precursor (I) is a precursor (la) which is characterized throughR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is an amino group; and intermediates of the formula (II) are characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs'alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent, a diazo substituent, or an amino group.[3] The process according to claim 1 or 2, wherein the precursor (I, la) is reacted to provide an intermediate (Ila) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a diazo substituent or an amino group.[4] The process according to any one of claims 1 to 3, wherein the intermediate (II, Ila) is further reacted to a second intermediate (lib) characterized throughR1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is hydrogen; andX is a fluoro substituent; and wherein the second intermediate (lib) is further reacted via an esterification to form a third intermediate (lie) wherein:R1is a halogen group or a pseudohalogen group, preferably a halogen group; andR2is a methyl substituent; andX is a fluoro substituent.[5] The process according to any one of claims 1 to 4, wherein the precursor (la) is a precursor(la’):(la’); and / or the intermediate (Ila) is an intermediate (Ila’) or an intermediate (Ila”):and / or the intermediate (Hb) is an intermediate (Hb’):(Hb’); and / or the intermediate (He) is an intermedi[6] The process according to claim 4, wherein the reaction comprises a halogenation step using a halogenation agent, or a pseudohalogenation step using a pseudohalogenation agent, and a diazotization step using a diazotization agent, and a fluorination step using a fluorination agent, and optionally an aqueous work up.[7] The process according to claim 6, wherein the fluorination agent, is Olah’s reagent and wherein the diazotization agent is NaNO2 or tert-butyl nitrite.[8] The process according to any one of claims 1 to 7, which further comprises an aqueous work-up after the fluorination step, which comprises the addition of an anhydrous alkali fluoride, preferably anhydrous KF, to the reaction mixture.[9] The process according to claim 1 , wherein the precursor (I) is a precursor (lb) and is characterized throughR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent; andIntermediates of the formula (II) are intermediates (lid) characterized through R1is a substituted or unsubstituted alkoxy- or aryloxycarbonyl group; andR2is hydrogen, a linear or branched Ci-Cs-alkyl, or a substituted or unsubstituted phenyl group; andX is a fluoro substituent.[10] The process according to claim 9, wherein the precursor (I, lb) is reacted with an organic acid anhydride (IV):R3 R3'\OZ(IV) whereinR3and R3’ are the same or different and independently represent the same or different organic leaving groups, preferably with trifluoro acetic acid (TFAA).[11] The process according to claim 10, wherein the organic acid anhydride (IV) is trifluoro acetic acid (TFAA):(TFAA).[12] The process according to any one of claims 9 to 11 , wherein the precursor (lb) is a precursor (lb’) and intermediate (lid) is an intermediate (lid’):(lb’) (lid’).[13] The process according to any one of claims 1 to 12, wherein MFA (III) is isolated from the reaction mixture by an elimination reaction.[14] A process for preparing patiromer calcium sorbitex comprising,(i) preparing methyl 2-fluoro acrylate (III) by the process according to any one of claims 1 to 13, and(ii) forming a polymerization reaction mixture comprising divinyl benzene, 1 ,7- octadiene and the MFA (III) to form crosslinked alkyl(2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer;(iii) deprotecting the crosslinked alkyl(2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer to form crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer; and(iv) contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer with a calcium salt to form crosslinked (calcium 2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer; and(v) swelling the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer and contacting with sorbitol to form patiromer calcium sorbitex.[15] The process according to claim 14, wherein the polymerization reaction mixture comprises divinyl benzene, 1 ,7-octadiene, the MFA (III) and a polymerization initiator, which is preferably lauroyl peroxide; and wherein the (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer formed is crosslinked (sodium 2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer; and wherein contacting the crosslinked (2-fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer with a calcium salt to form crosslinked (calcium 2-fluoroacrylate)- divinylbenzene-1 ,7-octadiene polymer comprises slurrying the crosslinked (2- fluoroacrylate)-divinylbenzene-1 ,7-octadiene polymer with a calcium salt, preferably with CaCh, CaBr2, or Cal2 or a combination thereof; andwherein the swelling of the crosslinked (calcium 2-fluoroacrylate)-divinylbenzene-1 ,7- octadiene polymer comprises slurrying the polymer in a solution comprising sorbitol, preferably in an aqueous sorbitol solution.

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