Process for the purification of 2-amino-1,3-propanediol (serinol)

Abstract

The invention relates to an industrial process for the purification of 2-amino-1,3- propanediol (serinol), which is a useful intermediate in the preparation of pharmaceutical and diagnostic products. In particular, the process of the invention relates to the separation of serinol from mixtures comprising low amounts of impurities (e.g. other aminoalcohol compounds), through reaction with a boronic acid and precipitation of the corresponding zwitterionic boronate ester. The invention also relates to the hydrolysis of such boronate ester and recycling of the recovered boronic acid.

Description

[0001] PROCESS FOR THE PURIFICATION OF 2-AMINO-l,3-PROPANEDIOL (SERINOL)

[0002] The invention relates to an industrial process for the purification of 2-amino-l,3- propanediol (serinol), which is a useful intermediate in the preparation of pharmaceutical and diagnostic products. In particular, the process of the invention relates to the separation of serinol from mixtures comprising low amounts of impurities (e.g. other aminoalcohol compounds), through reaction with a boronic acid and precipitation of the corresponding zwitterionic boronate ester. The invention also relates to the hydrolysis of such boronate ester and recycling of recovered boronic acid.

[0003] Background of the invention

[0004] Serinol is a key reagent employed in the synthesis of different compounds, like antiinflammatory, analgesic and cosmetic products, and in the synthesis of non-ionic X-ray contrast agents. Such contrast media are useful in the visualization of pathologies using diagnostic techniques (e.g. radiography, tomography), relying on the absorption of X-rays by the tissues or organs.

[0005] In particular, serinol represents a key building block for the preparation of lopamidol ( / V, / V / -bis[2-hydroxy-l-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-l-oxopropyl]amino]- 2,4,6-triiodo-l,3-benzenedicarboxamide), a radiographic contrast agent well known and widely used in daily diagnostic practice (The Merck Index, 15thEd.; RSC Publishing 2013, pp. 940-941). For a general reference to the synthetic route in the industrial preparation of lopamidol see for instance US 4,001,323.

[0006] As known, when dealing with pharmaceutical or diagnostic compounds, like the X-ray contrast media, the Regulatory authorities impose strict guidelines and standards regarding the purity of the products, as well as intermediates and starting materials thereof, to ensure their safety, efficacy and quality. For instance, specifications, acceptance criteria and analytical methods for assessing the purity of pharmaceutical compounds and products are defined in the guidelines established by the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.) and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). These authorities require drugs with very low level of impurities, mostly in order to minimize any involved risk of side-effects or toxic effects for the patient.

[0007] In particular, when dealing with contrast agents, the purity requirement is of utmost importance due to the fact that these products can be administered with a dosage much higher than that of other medicaments. For instance, an amount up to 150 g or even higher can be administered in a single dose.

[0008] To facilitate the assessment of the purity level of these diagnostic compounds, the purity of the reagents and starting materials, like serinol, also plays a crucial role in the pharmaceutical manufacturing processes, in order to avoid formation of any by-product and assure high purity standards to the final products.

[0009] However, the purification of serinol is not trivial, particularly due to its high boiling point. In fact, at room temperature it is in a solid form, with a melting point of 52-55 °C and it displays at atmospheric pressure the very high boiling point of 277 °C.

[0010] According to the published literature, serinol can be synthesized in different ways (see for instance AndreeBen and Steinbiichel, AMB Express 2011, 1: 12); in particular, the industrial preparation of serinol is mainly carried out with a two-step procedure, involving the condensation of nitromethane and formaldehyde, followed by Pd / C promoted catalytic hydrogenation of the nitro group in 2-nitro-l,3-propanediol intermediate (e.g. as described in US 4,448,899), according to the reaction Scheme 1 as described below:

[0011] A O NOn catalyticN Hl hydrogenation |

[0012] H- - HO^ ^OH - ». HO^ ^OH nitromethane formaldehyde 2-nitro-l,3-propanediol 2-amino-l,3-propanediol

[0013] (serinol)

[0014] Scheme 1

[0015] However, some procedures for the synthesis of serinol may lead also to the formation of organic impurities including glycerol and aminoalcohol compounds like ethanolamine, tris(hydroxymethyl)aminomethane (Tris base), 2-(methylamino)-l,3-propanediol and 1- amino-2,3-propanediol (isoserinol), which are difficult to be separated and eliminated. In particular, the removal of isoserinol can be particularly challenging due to its physicochemical features very similar to those of serinol (WOOl / 58848).

[0016] To this purpose, different procedures for the purification of serinol have been investigated in the past and are reported in the literature, depending on the type and content of the impurities derived from the alternative synthetic processes. For instance, it has been conveniently purified by precipitation as oxalate salt (WO98 / 24755); by precipitation as Shiff base with benzaldehydes (WOOl / 58848) or by distillation (e.g. as described in US 4,448,999; US 5,053,545; US 4,221,740).

[0017] Currently the most widely used procedure for the purification of serinol requires multiple distillations under high vacuum. The performance of this purification process, particularly on industrial scale, can be inefficient and highly demanding, for instance in terms of equipment, energy consumption and time required for the intensive distillation steps or the expensive catalysts used. Therefore, a serinol product characterized by the highest standards of purity can be obtained only through a costly and challenging process that leads to relatively high retail price (AndreeBen and Steinbiichel, AMB Express 2011, 1: 12; US 4,448,999). For this reason, the suppliers generally declare a purity of serinol not higher than 98%- 99%, a value that is considered unsatisfactory for the use in the preparation of X-ray contrast agents.

[0018] It is therefore important to provide new straightforward and cost-effective methods for the selective purification of serinol from the above-mentioned impurities.

[0019] Besides the above-mentioned disclosures, recently a new procedure has been described by A. Leon-Negrete et al., J. Mex. Chem. Soc. 2022; 66(4):421-432, where the formation of heterocyclic zwitterionic boronate esters derived from carbonylphenylboronic acids and amino-diols was investigated, mainly for research purposes. In particular, the condensation reaction between serinol and 3- or 4-formyl / acetylphenylboronic acids in a methanol / acetone mixture was observed and the zwitterionic adducts thus formed were characterized by spectroscopic and crystallographic analysis. The product was purified and obtained as white solid, but the efficiency of the method appeared unsatisfactory (yields not higher than 69%) and no indication about the purity was provided, therefore the disclosure does not represent an actual solution to the problems mentioned before, particularly in case of industrial manufacturing. Indeed, the purification of serinol was not the purpose of this paper, as no mention was made about the hydrolysis and recovery of serinol after precipitation of the adduct with boronic acid.

[0020] Surprisingly, it was found that the formation of zwitterionic adducts between serinol and a boronic acid in an aqueous environment is a selective reaction that can be conveniently exploited for an easy, efficient and sustainable purification of serinol from the impurities formed during its synthesis. In fact, it was found that said boronate esters of serinol tend to selectively precipitate as solid in water, while the corresponding condensation products with the known serinol impurities (e.g. other aminoalcohols) remain in solution. The precipitate, easily recovered by filtration, can be then hydrolyzed and processed, for instance through an ion exchange resin, to give pure serinol as desired, as well as the pure boronic acid that can be recycled for further purifications.

[0021] Therefore, the process of the invention, with the use of simple condensation and hydrolysis reactions, allows to effectively overcome the mentioned problems related to high costs and low efficiency of difficult methods, and can represent a valuable alternative allowing to reduce manufacturing costs and energy-consumption and at the same time providing a final product with remarkable high yields and purity.

[0022] Summary of the invention

[0023] In a first aspect, the aim of the present invention is to provide an alternative process for the purification of 2-amino-l,3-propanediol (serinol) that is simple and advantageously provides a saving of manufacturing costs. In fact, the process of the invention avoids the use of expensive and energy-consuming devices, like the industrial systems for distillation under vacuum, and represents a sustainable and circular process, as it involves the use of environmentally friendly solvents like water while allowing to recover and reuse the starting reagents.

[0024] Accordingly, the invention provides a simple and economic process for the purification of serinol by reacting the crude product obtained from its synthesis with a suitable boronic acid in an aqueous solution, optionally in the presence of a base and / or a small amount of an alcohol solvent.

[0025] Based on the present invention, serinol can be obtained with an acceptable purity level, using a process also applicable on industrial scale production. In fact, it was surprisingly found that the zwitterionic boronic esters of serinol are insoluble in aqueous environment and can be separated and purified from the by-products and impurities of its manufacturing by selective precipitation and filtration of a serinol insoluble adduct.

[0026] This advantageously makes the purification process of the invention a straightforward, cheap and environmentally friendly method, which can conveniently replace, particularly in an industrial set up, the difficult and energetically demanding procedures currently in place and allows to remove the main impurities providing 2-amino-l,3-propanediol with high purity. The process of the present invention is also advantageous because the boronic acid reagent can be conveniently recovered after the hydrolysis of the corresponding boronic ester and recycled in a subsequent purification step.

[0027] Moreover, the present invention further relates to the use of optionally substituted phenyl boronic acids for the purification of 2-amino-l,3-propanediol.

[0028] Brief Description of the Drawing

[0029] Figure 1 illustrates a preferred embodiment in order to carry out the present invention, by a schematic representation.

[0030] Detailed Description of the Invention

[0031] According to a first aspect, the present invention relates to a process for the purification of 2-amino-l,3-propanediol (serinol), or a base or salt thereof, in a mixture comprising polyols and / or aminoalcohol impurities, said process comprising the following steps: a) reacting 2-amino-l,3-propanediol with a boronic acid of formula (I) wherein Ri and R.2 are independently selected from hydrogen, halogen and straight or branched Ci-Ce alkyl or Ci-Ce alkoxy, to provide the derivative of formula (II) wherein Ri and R2 are as defined above; b) hydrolyzing the intermediate of formula (II), to provide a solution of pure 2-amino- 1,3-propanediol; wherein step a) is carried out in water, at a temperature comprised between 50 °C and 120 °C.

[0032] Preferably, the reaction of step a) is carried out with a boronic acid of formula (I) wherein both groups Ri and R.2 are hydrogen.

[0033] In another preferred embodiment Ri is hydrogen and R2 is selected from methyl, ethyl, propyl, tert-butyl, methoxy and chloro.

[0034] In another preferred embodiment boronic acid of step a) has the following formula (la) wherein both Ri and R2 are methyl, ethyl, propyl or tert-butyl.

[0035] Preferably step a) is carried out at a temperature comprised between 70 °C and 110 °C or more preferably between 80 °C and 100 °C. Even more preferably the reaction of step a) is carried out at 90 °C.

[0036] Preferably step a) is carried out by adding to the mixture a base selected from NaOH, KOH, Ca(OH)2, NaHCOs, KHCO3, NaCOs, CaCOs, K2CO3 and the like. More preferably, step a) is carried out in water in the presence of NaOH or K2CO3. In a preferred embodiment the molar ratio between the base and serinol is comprised between 0.3: 1 and 1 : 1.

[0037] In another preferred embodiment, step a) is carried in water in the presence of a suitable amount of a solvent, with or without the base described above. Preferably, said solvent is an alcohol selected from methanol, ethanol, propanol, 2-propanol, butanol, and the like. More preferably the solvent is 2-propanol.

[0038] Preferably, said solvent is present in an amount comprised between 1% and 20% v / v. More preferably, an amount of 10% v / v of solvent is added (e.g. 10% v / v of 2- propanol). In a preferred embodiment the molar ratio between 2-amino-l,3-propanediol and the boronic acid of formula (I) in step a) is at least 1: 1.

[0039] Preferably the intermediate of formula (II) formed in step a) is isolated by precipitation and collected by filtration of the mixture of step a).

[0040] The hydrolysis of step b) is preferably carried out in an aqueous acidic solution, for instance by adding an acid selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acid and the like.

[0041] Optionally, in the process of the invention, step b) is followed by step c) relating to a further purification of the 2-amino-l,3-propanediol obtained from step b) through ion exchange chromatography.

[0042] The optional purification of step c) is preferably carried out by eluting the solution of 2-amino-l,3-propanediol obtained from step b) through a column packed with a suitable ion exchange resin. Preferably, after completion of the chromatography, the purified 2- amino-l,3-propanediol is recovered by adding a base, such as for instance aqueous ammonia.

[0043] Optionally, the purification of said step c) through ion exchange chromatography can be preceded by the elution of the solution of 2-amino-l,3-propanediol obtained from step b) through a suitable scavenger resin (step i), to remove any possible residual of boronic acid.

[0044] According to these last embodiments, the invention relates to a process for the purification of 2-amino-l,3-propanediol (serinol), or a base or salt thereof, comprising the following steps: a) reacting 2-amino-l,3-propanediol, in a mixture comprising polyols and / or aminoalcohol impurities, with a boronic acid of formula (I) wherein Ri and R.2 are independently selected from hydrogen, halogen and straight or branched Ci-Ce alkyl or Ci-Ce alkoxy, to provide the derivative of formula (II) wherein Ri and R.2 are as defined above; b) hydrolyzing the intermediate of formula (II) to provide a solution of pure 2-amino-l,3- propanediol; and optionally i) eluting said solution of pure 2-amino-l,3-propanediol through a scavenger resin; and / or c) purifying the 2-amino-l,3-propanediol obtained from step b) or i) through ion exchange chromatography; wherein step a) is carried out in water at a temperature comprised between 50 °C and 120°C.

[0045] In another aspect, the present invention relates to a process as described above wherein the boronic acid of formula (I) is recovered from step b) and optionally recycled in the reaction of step a). Such reagent can be recovered as solid by filtrating the mixture obtained from the hydrolysis of step b). The boronic acid of formula (I) thus recovered can be re-used as such or purified before the recycling in a subsequent reaction batch.

[0046] A further aspect of the present invention relates to the use of the pure serinol, obtained as described above, for the preparation of a non-ionic X-ray contrast agent.

[0047] Moreover, the invention generally relates to the use of the boronic acid of formula (I) as defined above for the purification of 2-amino-l,3-propanediol by means of the formation of the intermediate of formula (II) as defined above in water at a temperature comprised between 50 °C and 120 °C, followed by hydrolysis of said intermediate.

[0048] The process of the present invention also encompasses hydrates, solvates, organic or mineral salts of the compounds described above, particularly of 2-amino-l,3-propanediol, the boronic acids of formula (I) and the zwitterionic adducts of formula (II).

[0049] In the context of the present invention, the expression "straight or branched Ci-Ce alkyl" refers to saturated hydrocarbon groups containing from 1 to 6 carbon atoms respectively, which may be linear or branched. Preferably, the alkyl groups are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

[0050] The term "Ci-Ce alkoxy" refers to an alkoxy group comprising a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Preferably the methoxy group is used. The expression "alcohol solvent" refers to a solvent bearing one or more hydroxyl (- OH) function attached to a carbon atom of an alkyl group and includes primary, secondary and tertiary alcohols. Preferred examples of alcohol solvents used in the invention include methanol, ethanol, propanol, isopropanol, butanol and the like.

[0051] The expression "polyols and / or aminoalcohol impurities" refers to organic compounds that may be formed as by-products during the preparation of serinol according to manufacturing processes known in the art. Such impurities are in particular organic molecules bearing one or more hydroxyl groups, e.g. diols ortriols, and optionally an amino group. Preferred examples of such polyols and / or aminoalcohol impurities include glycerol, ethanolamine, tris(hydroxymethyl)aminomethane (Tris base), 2-(methylamino)-l,3- propanediol and l-amino-2,3-propanediol (isoserinol).

[0052] The phenyl-boronic acids of formula (I) used in the present invention are well-known compounds which are commercially available or can be prepared according to literature methods.

[0053] According to the invention, the reaction of step a) may be carried out in a reactor with mechanical stirring using essentially water as solvent, optionally in the presence of a base. For instance, a suitable base is selected from NaOH, KOH, Ca(OH)2, NaHCOs, KHCO3, NaCOs, CaCOs, K2CO3 and the like. More preferably, step a) is carried out in water in the presence of NaOH or K2CO3. In a preferred embodiment the molar ratio between the base and serinol is comprised between 0.3: 1 and 1: 1.

[0054] More preferably, the base is added in stoichiometric amount (1: 1) and the molar ratio among the crude serinol, the boron ic acid of formula (I) and the base is 1 : 1: 1. Adding the base can be useful to reduce the acidity of the solution due to the presence of the boronic acid and to keep it at a pH preferably comprised between 5 and 9, more preferably between 6 and 8.

[0055] During the reaction step a), the condensation product of formula (II), formed between serinol and the boronic acid, tends to selectively precipitate so that it can be easily separated. The isolation of the intermediate of formula (II) is preferably performed by filtration. Surprisingly, it was found that the corresponding condensation products formed between the boronic acid (I) and the other aminoalcohol impurities (including isoserinol) are characterized by a higher solubility and remain dissolved in the aqueous solution.

[0056] Therefore, the solid boronate ester of formula (II) is let to precipitate for a time comprised between 2 and 25 hours and at a temperature comprised between 50 °C and 120 °C before filtering the solid thus formed. In a preferred embodiment, the reaction of step a) is carried out at 90 °C for at least 3 hours.

[0057] To foster such precipitation and accelerate the reaction time, a small amount of an alcohol solvent can be added to the solution. Accordingly, in a preferred embodiment, step a) can be performed in water, with or without the presence of a base, with the addition of a suitable amount of an alcohol solvent, e.g. lower than 20% v / v, preferably selected from methanol, ethanol, propanol, 2-propanol, butanol, and the like. Said amount of alcohol solvent can be added at the beginning of step a) or optionally in a second moment only, preferably at the end of the condensation reaction, if needed to promote crystallization of the serinol boronate ester.

[0058] Preferably in step a) the molar ratio between 2-amino-l,3-propanediol and the boronic acid of formula (I) is stoichiometric and corresponding to at least 1: 1. More preferably, the amount of boronic acid equivalents is at least equal to the total amount of equivalents of the aminoalcohol species present in the mixture, including isoserinol and other impurities.

[0059] According to step b) of the invention, the boronate ester of formula (II) can be hydrolyzed according to standard methods, preferably under acidic conditions. For instance, the hydrolysis can be performed by adding the solid obtained from step a) to a solution comprising an acid, for instance selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acid, and heating the mixture to a temperature comprised between 20 °C and 70 °C for a time comprised between 5 and 30 minutes. Preferably, hydrolysis is carried out by heating the mixture at about 30-60 °C, preferably at 30 °C for about 30 minutes, after addition of a HCI 20% w / w solution in water. After cooling the reaction mixture, the precipitation of a white solid is observed corresponding to the boronic acid of formula (I).

[0060] To obtain a quantitative recovery of the boronic acid of formula (I), hydrolysis is preferably carried out using a stoichiometric amount of the acid (e.g. HCI) and heating the solution at a temperature not higher than 30 °C for 30 minutes or less. Stronger acidic conditions could lead to degradation of the boronic acid with formation of boric acid and the corresponding benzene derivative.

[0061] After the hydrolysis of step b), the solid comprising the recovered boronic acid of formula (I) can be separated from the liquid mixture comprising 2-amino-l,3-propanediol. For instance, this can be accomplished by filtering the solid under reduced pressure. The liquid mixture comprising hydrolyzed serinol can be then evaporated under reduced pressure to recover pure serinol or a salt thereof.

[0062] If necessary, to obtain the purified serinol after the hydrolysis step, the reaction liquid mixture can be optionally treated with an ion exchange resin, followed by evaporation of the solvent. Suitable resins can be preferably selected among strongly cationic resins and / or weak anionic resins, that are loaded into a column before the liquid phase is eluted through it.

[0063] In some cases, when traces of boronic acid of formula (I) are still present in the liquid phase after filtration of the hydrolysis mixture, such chromatography onto ion exchange resins (step c) can be preceded by an optional further purification through a suitable scavenger resin, that is able to separate and retain the boronic acids (step i). Typically, to this purpose, polymeric (e.g. styrene / divinylbenzene) resins functionalized with diolic functions, polyalcohols or poly-hydroxylated groups, like methylglucamine, are especially preferred, as specifically designed to boric or boronic acids removal through complexation and subsequent sequestration. For instance, Amberlite™ IRA743, Lewatit® MK51, Diaion™ CRB03 or / V' / V-diethanolaminomethyl polystyrene or other equivalent commercial resins can be conveniently selected, based on the common knowledge on this matter.

[0064] Alternatively, such step on the scavenger resin (step i) may be skipped as unnecessary, in particular when all the residual boronic acid of formula (I) is already removed by filtration or when the resin selected for the ion exchange chromatography is also able to remove any boronic acid traces.

[0065] In step c) the solution obtained from step b) or step i) is preferably loaded onto a strongly cationic exchange resins, for instance having sulphonic acid functional groups bound to a polymeric (styrene-divinylbenzene) matrix material, such as Amberlite™ IRA- 900, Amberlite™ IR120 or Duolite™ C20MB, to retain serinol, for instance as described in patent US 4,503,252.

[0066] Once the elution is completed, serinol can be released with a diluted aqueous basic solution, such as for instance aqueous ammonia and the like; then the eluate can be evaporated to give pure serinol.

[0067] The recovery of the boronic acid of formula (I) after the hydrolysis of the boronic ester of formula (II) can be carried out simply by filtration of the solid precipitated during or at the end of the hydrolysis step b). If necessary, the recovered boronic acid of formula (I) can be purified before being recycled in a subsequent batch according to known methods.

[0068] Accordingly, the boronic acid of formula (I) used in the above embodiments of the process is recovered as described above and preferably recycled in step a) of the process.

[0069] The analytical characterization of the product can be done according to well-known methods, for example gas chromatography, melting point and spectroscopy such as NMR and IR, as better detailed in the Experimental Section.

[0070] The process of the invention can be performed using different boronic acids of formula (I) and different conditions. The following examples illustrate some preferred and representative conditions to carry out the invention disclosed herein.

[0071] Experimental part

[0072] All the starting materials mentioned above are commercially available or were purchased from Sigma-Aldrich or TCI Europe.

[0073] In the following examples crude serinol was purchased from a supplier or prepared following the procedure described in US 4,448,899, i.e. by reaction of nitromethane with formaldehyde followed by catalytic hydrogenation of the nitro group.

[0074] Analytical Methods

[0075] The reaction mixtures and the products were analysed by GC-MS using the following method (also described in Musu C. et al, Journal of Chromatography A (1988), 449, 432- 439):

[0076] 5 mg of product were cooled at 0 °C in a sealable vial and 2 mL of trifluoroacetic anhydride were carefully added. The mixture was warmed at room temperature and the content stirred for 30 min. The clear solution was transferred in a GC-MS vial and analysed with the following conditions:

[0077] GC Column: Agilent J&W HP-5MS Ultra Inert, 30 m x 0.25 mm, 0.25 pm

[0078] Injection volume: 1 pL

[0079] Inlet mode: split (split ratio 20: 1)

[0080] Solvent delay: 1 min

[0081] Temperature programme: initial isotherm at 80 °C for 5 min; first ramp from 80 °C to 100 °C at 5 °C / min; second ramp from 100 °C to 220 °C at 20 °C / min.

[0082] All percentages are by weight unless otherwise indicated.

[0083] Example 1

[0084] Step a) Condensation of serinol with a boronic acid of formula (I)

[0085] 1A: Condensation of serinol with phenylboronic acid (water, NaOH)

[0086] Serinol (0.911 g, 10 mmol), phenyl boronic acid (1.22 g, 10 mmol) and NaOH (0.40 g, 10 mmol) were dispersed in 20 mL of deionized water under magnetic stirring. The solution was heated at 90 °C for 12 hours. After 6 days, a white precipitate was slowly formed and recovered by Buchner filtration (recovered 1.5 g; Yield: 64.9%; m.p. : 140- 145 °C)

[0087] IB: Condensation of serinol with phenylboronic acid (water and 2-PrOH, no base)

[0088] Crude serinol (1 g, 11 mmol) and phenyl boronic acid (1.36 g, 11 mmol) were dispersed in 22 mL of deionized water under magnetic stirring. The solution was heated at reflux. After 2 hours, 2.2 mL of 2-propanol were added. The formation of a white crystal solid was observed and after 2 hours such precipitate was recovered by Buchner filtration under reduced pressure and dried in a vacuum oven at 40°C overnight (recovered 2.10 g; Yield: 98%).

[0089] 1C: Condensation of serinol with 4-ter-butyl-PBA (water, K2CO3)

[0090] Crude serinol (2.22 g, 24.4 mmol), 4-tert-butylphenylboronic acid (2.67 g, 24.4 mmol) and K2CO3 (1.67 g, 12.1 mmol) were dispersed in 50 mL of deionized water under magnetic stirring. The solution was heated at 90 °C. After 6 hours, the solution was cooled at room temperature and a white crystalline solid was filtered under reduced pressure. The solid was dried in a vacuum oven at 40 °C overnight (5.93 g; Yield: 96.8%; m.p. : 122-128 °C).XH NMR (400 MHz, CD3CN): 6 7.68 (d, J =8.3 Hz, 2H), 7.42 (d, 1=8.4 Hz, 2H), 4.14 (dd, J= 10.8, 4.0 Hz, 2H), 3.73 (dd, 1 = 10.8, 7.3 Hz, 2H), 3.26-3.18 (m, 1H), 1.33 (s, 9H).

[0091] ID: Condensation of serinol with 3,5-dimethyl-PBA (water, K2CO3)

[0092] Crude serinol (0.728 g, 8 mmol), 3,5-dimethylphenylboronic acid (1.2 g, 8 mmol) and K2CO3 (0.552 g, 4 mmol) were dispersed in 23 mL of deionized water under magnetic stirring. The dispersion was heated at 90 °C for 6 hours (no complete dissolution was observed). Afterwards, the dispersion was cooled at room temperature and filtered under reduced pressure. The white solid thus recovered was dried in a vacuum oven at 40 °C overnight (1.30 g; Yield: 72.8%).

[0093] XH NMR (400 MHz, CD3CN): 6 7.35 (s, 2H), 7.10 (s, 1H), 4.13 (dd, 1 = 10.8, 4.0 Hz, 2H), 3.72 (dd, 1 = 10.8, 7.2 Hz, 2H), 3.26-3.18 (m, 1H), 2.31 (s, 6H).

[0094] IE: Condensation of serinol with 3-methyl-PBA (water, K2CO3)

[0095] Crude serinol (0.91 g, 10 mmol) and 3-methylphenylboronic acid (1.35 g, 10 mmol) were suspended in 20 mL of deionized water. Then K2CO3 (621 mg, 5 mmol) was added and the solution was heated at 90 °C for 3 hours. Afterwards, the solution was cooled at room temperature and the formation of a white solid was observed. The precipitate was isolated by filtration under reduced pressure and dried in a vacuum oven at 40 °C overnight (1.56 g; 7.5 mmol; Yield: 75%).

[0096] XH NMR (400 MHz, CD3CN): 6 7.6-7.5 (m, 2H), 7.30-7.25 (m, 2H), 4.15 (dd, 1 = 10.7, 3.8 Hz, 2H), 3.74 (dd, 1 = 10.8, 7.2 Hz, 2H), 3.23 (quint, 1H, 1 = 7.2 Hz), 2.35 (s, 3H).

[0097] IF: Condensation of serinol with phenylboronic acid (water, no base, no solvent)

[0098] A mixture of serinol (9.10 g, 100 mmol) and isoserinol (15.03 g, 165 mmol) was dispersed in 265 mL of deionized water under magnetic stirring together with phenylboronic acid (32.33 g, 265 mmol). The solution was heated to 90 °C, initially appearing as a dispersion before becoming a clear solution. The mixture was heated for 4 hours and then cooled to room temperature. A white precipitated formed, which was filtered over Hirsh filter funnel and crystallized from water (50 ml). The solid thus obtained was dried in a vacuum oven at 40 °C for 16 hours (19.0 g; Yield: 97.4%).

[0099] Step b) Hydrolysis

[0100] 24 g (123 mmol) of the phenylboronic ester obtained from step a) in each of the examples described above were suspended in 120 mL of HCI 5% w / w. The mixture was heated at 30 °C for 30 minutes to obtain a clear solution. Then the mixture was cooled at room temperature and the formation of a white solid was observed. The precipitate was isolated by filtration under reduced pressure and identified as the recovered phenyl boronic acid (14.4 g, 118 mmol; 95.9 %). The filtered solution was evaporated under reduced pressure to obtain a white solid, identified byXH-NMR as serinol hydrochloride (15.6 g, quantitative). The solid was then dissolved in 140 ml of deionized water and eluted through a column packed with 150 g of an Amberlite S-900 hydroxy resin. The column was further eluted with IL of deionized water and the combined eluate was evaporated to dryness to give 11 g of serinol as a white solid. (GC-MS purity 99.0 %, isoserinol content below 0.6 %).

[0101] Example 2

[0102] Preparation of crude serinol starting from nitromethane and paraformaldehyde .

[0103] In a 1 L reactor equipped with mechanical stirring, a thermometer, a dosing funnel and a condenser, 110.0 g of methanol, 1.24 g (31 mmol) of NaOH and 39.1 g (1.235 mol) of paraformaldehyde (95% titer) were added. The mixture was stirred at 25 °C for 10 min, obtaining a clear solution. 37.5 g (0.614 mol) of nitromethane was added over 30 min, maintaining the mixture temperature below 30°C with a cold-water bath. After the addition, a solution containing 23.4 g (0.584 mol) of NaOH in 118 g of methanol was added dropwise, while keeping the reaction temperature below 30 °C. During the addition, the gradual formation of a white solid was observed. After 1 h the thick suspension was filtered through a sintered glass filter. The solid was washed with methanol (2 X 100 mL) and dried in a vacuum oven at 30 °C overnight. 118 g of white solid corresponding to 2-nitro-l,3- propanediol sodium salt were obtained (0.57 mol, yield: 93%), containing two molecules of MeOH per molecule of product.

[0104] In a steel autoclave, the 2-nitro-l,3-propanediol sodium salt (5.00 g, 24.14 mmol) was dissolved in a mixture of glacial acetic acid (7 mL), deionized water (15 mL) and MeOH (0.5 mL). The clear solution was degassed and 500 mg of Pd / C 5% w / w (50% w / w wet) were added. The mixture was pressurized at 50 atm of H2 and temperature was raised to 55 °C. After 2 h, the mixture was filtered through a pad of celite to remove the catalyst and all volatiles were removed. The crude (a waxy solid) was taken up with 20 mL of water and adsorbed on a Amberlite IR 120 column. The resin was washed with 0.6 L of deionized water and the serinol was recovered by eluting with 2 N NH4OH, followed by water. After evaporation of all volatiles, the resulting white solid was dissolved in 30 mL of refluxing ethanol. Gaseous HCI was bubbled in the solution until complete precipitation of a white solid, which was recovered by filtration. The serinol hydrochloride was dissolved in water, adsorbed again on Amberlite IR 120 and recovered as the free base by elution with 2 N NH4OH. Crude serinol was obtained as a white solid (1.54 g, 16.9 mmol, 70 % yield).

[0105] Step a) Condensation of serinol with a boronic acid of formula (I)

[0106] Crude serinol (1.54 g, 16.9 mmol) obtained as described before was dissolved in deionized water (17 mL) and phenylboronic acid (2.06 g, 16.9 mmol) was added as a solid. The resulting white suspension was heated at 90 °C for 2 h observing complete dissolution followed by the precipitation of a white solid. Mixture was cooled to about 5 °C and the white precipitate was filtered off. Overnight vacuum drying at 65 °C gave the phenylboronic ester of serinol as the monohydrated form (3.13 g, yield 95%).

[0107] Step b) Hydrolysis

[0108] The white powder obtained from step a) was suspended in 20 mL of deionized water and the suspension was warmed at 30 °C. HCI 20% w / w (4 mL) was slowly added observing complete dissolution, followed by gradual precipitation of a white solid. After 30 min, the mixture was cooled at 5 °C and the white precipitate was recovered by suction filtration and oven dried to give 2 g of phenylboronic acid (16.5 mmol). The filtrate was eluted through a column packed with Amberlite S-900 hydroxy resin, to give pure serinol as a white solid (1.45 g, 94 % yield).

[0109] Comparative Example (with conditions described in J. Mex. Chem. Soc. 2022; 66(4):421-432}

[0110] Condensation of serinol with phenylboronic acid in MeOH

[0111] Serinol (1.64 g, 18 mmol) and phenylboronic acid (2.19 g, 18 mmol) were suspended in 18 ml of MeOH. The mixture was stirred at room temperature for 1 hour, then left unstirred overnight. The resulting white solid was isolated by suction filtration and over dried overnight until a constant weight of 0.82 g was obtained. The precipitate showed a melting point of 104-111 °C and from the analysis ofXH-NMR (DMSO-de) spectrum resulted corresponding to a mixture of serinol-phenyl boronic acid condensation product (II) and unreacted phenylboronic acid (I), with a molar ratio of 9: 1 respectively. The calculated yield of the serinol-phenyl boronic acid condensation product (II) was 21%.

[0112] References

[0113] 1. The Merck Index, 15thEd.; RSC Publishing 2013, pp. 940-941

[0114] 2. US 4,001,323

[0115] 3. AndreeBen and Steinbiichel, AMB Express 2011, 1 : 12

[0116] 4. US 4,448,899

[0117] 5. WO98 / 24755

[0118] 6. WOOl / 58848

[0119] 7. US 4,448,999

[0120] 8. US 5,053,545

[0121] 9. US 4,221,740

[0122] 10. Leon-Negrete A. et al., J. Mex. Chem. Soc. 2022; 66(4):421-432

[0123] 11. US 4,503,252

[0124] 12. Musu C. et al., Journal of Chromatography A (1988), 449, 432-439

Claims

CLAIMS1. A process for the purification of 2-amino-l,3-propanediol (serinol), or a base or salt thereof, in a mixture comprising polyols and / or aminoalcohol impurities, said process comprising the following steps: a) reacting 2-amino-l,3-propanediol in said mixture with a boronic acid of formula (I)wherein Ri and R2 are independently selected from hydrogen, halogen or straight or branched Ci-Ce alkyl or Ci-Ce alkoxy, to provide the intermediate of formula (II)wherein Ri and R2 are as defined above, b) hydrolyzing said intermediate of formula (II) to provide a solution of pure 2-amino-1,3-propanediol; wherein step a) is carried out in water, at a temperature comprised between 50 °C and 120 °C.

2. The process according to claim 1 wherein both groups Ri and R2 are hydrogen.

3. The process according to claim 1 wherein Ri is hydrogen and R2 is selected from methyl, ethyl, propyl, tert-butyl, methoxy and chloro.

4. The process according to claim 1 wherein the boronic acid of step a) has the following formula (la)wherein both Ri and R2 are methyl, ethyl, propyl or tert-butyl.

5. The process according to claim 1, wherein step a) is carried out at a temperature comprised between 70 °C and 110 °C.

6. The process according to claim 5, wherein step a) is carried out at 90 °C.

7. The process according to claim 1, wherein step a) is carried out in water in the presence of a base selected from NaOH, KOH, Ca(OH)2, NaHCOs, KHCO3, NaCOs, CaCOs and K2CO3.

8. The process according to claim 1 or 7, in which step a) is carried out in water with the addition of an amount of an alcohol solvent comprised between 1% and 20% v / v.

9. The process according to claim 1, wherein in step a) the molar ratio between 2-amino- 1,3-propanediol and the boronic acid of formula (I) is at least 1 : 1.

10. The process according to claim 1, wherein hydrolysis step b) is carried out with an acid selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acid.

11. The process according to claim 1 wherein the hydrolysis of step b) is carried out at 30 °C for 30 minutes, after addition of a HCI 20% w / w solution in water.

12. The process according to claim 1, further comprising the step of: c) purifying the 2-amino-l,3-propanediol obtained from step b) through ion exchange chromatography.

13. The process for the purification of 2-amino-l,3-propanediol (serinol) according to claim1 or 12, comprising: a) reacting 2-amino-l,3-propanediol, in a mixture comprising polyols and / or aminoalcohol impurities, with a boronic acid of formula (I)wherein Ri and R.2 are independently selected from hydrogen, halogen or straight or branched Ci-Ce alkyl or Ci-Ce alkoxy, to provide the intermediate of formula (II)wherein Ri and R2 are as defined above, b) hydrolyzing said intermediate of formula (II) to provide a solution of pure 2-amino- 1,3-propanediol;and optionally i) eluting said solution of pure 2-amino-l,3-propanediol through a scavenger resin and / or c) purifying the 2-amino-l,3-propanediol obtained from step b) or i) through ion exchange chromatography; wherein step a) is carried out in water, at a temperature comprised between 50 °C and 120 °C.

14. The process according to claim 1, wherein the boronic acid of formula (I) is recovered by filtration at the end of step b) and recycled in the reaction step a).

15. Use of a boronic acid of formula (I) as defined in claim 1 or 13 for the purification of2-amino-l,3-propanediol by means of the formation of the intermediate of formula (II) as defined above in water at a temperature comprised between 50 °C and 120 °C, followed by hydrolysis of said intermediate.

Images