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

Abstract

The invention relates to an industrial process for the purification of 3-amino-1,2- propanediol (isoserinol), 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 isoserinol from mixtures comprising small amounts of 2-amino-1,3- propanediol (serinol), through reaction with a boronic acid and separation of the serinol as precipitated boronate ester. The invention also relates to the hydrolysis of the remaining solution to obtain isoserinol purified from serinol and to the recovery and recycling of the boronic acid.

Description

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

[0002] The invention relates to an industrial process for the purification of 3-amino-l,2- propanediol (isoserinol), 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 isoserinol from mixtures comprising small amounts of 2-amino-l,3- propanediol (serinol), through reaction with a boronic acid and separation of the serinol as precipitated boronate ester. The invention also relates to the hydrolysis of the remaining solution to obtain isoserinol purified from serinol and to the recovery and recycling of the boronic acid.

[0003] Background of the invention

[0004] 3-amino-l,2-propanediol (isoserinol) is a key reagent employed in a wide variety of applications and for the synthesis of specialty materials, like antiinflammatories, analgesics and cosmetics.

[0005] In particular, it is widely used as building block in the synthesis of non-ionic iodinated X-ray contrast agents, such as lomeprol, lohexol, lodixanol, loversol, lopentol, lopromide and loxilan, which 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. For instance, it represents a key building block for the preparation of lomeprol, (N, N'-bis [2, 3-d ihydroxypropy I] -5(hydroxyacety I) methylamino] -2,4, 6-tri iodo- 1,3- benzenedicarboxamide), a radiographic contrast agent well known and widely used in daily diagnostic practice (A. Gallotti et al., Eur. J. Radiol. 1994, 18(S1), S1-S12). For a general reference to the synthetic route in the industrial preparation of lomeprol see for instance WOOO / 32561.

[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 l50 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 isoserinol, 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 isoserinol is not trivial, particularly due to its high boiling point. In fact, at room temperature racemic isoserinol is a viscous liquid, and it displays the very high boiling point of 264-265 °C at 739 mmHg.

[0010] According to the published literature, isoserinol can be synthesized in different ways. In particular, the industrial preparation of isoserinol is mainly carried out by exploiting the reaction of epichlorohydrine or 1,2-epoxypropanol (glycidol) or 3-chloro-l,2-propanediol (CPD) with ammonia (e.g. aqueous 25% w / w or gaseous) in alkaline environment, by adding sodium hydroxide (see for instance the disclosure of EP2673258 and US 4,360,697), for instance according to the reaction Scheme 1 as described below: serinol

[0011] Scheme 1

[0012] However, as shown in Scheme 1, the crude isoserinol prepared by this procedure may contain variable amounts of organic impurities, such as for instance glycerol; 3- chloropropane-l,2-diol; bis- and tert-hydroxyalkyl amines, like bis(2,3- dihydroxypropyl)amine and tert(2,3-dihydroxypropyl)amine; diethers and 2-amino-l,3- propanediol (serinol), as well as some polymeric materials and inorganic impurities and salts. In particular, among the organic impurities, serinol can be present as by-product in a sizeable amount and its removal is particularly challenging due to its physico-chemical features very similar to those of isoserinol (e.g. similar chemical structure and boiling point).

[0013] To this purpose, different procedures for the purification of crude isoserinol have been investigated in the past and reported in the literature, depending on the type and content of the impurities derived from the alternative synthetic processes. For instance, isoserinol has been conveniently purified by different steps of formation of salts with acids like hydrochloride, acid oxalate, benzoates and p-toluensulfonates, crystallization thereof and purification by ion exchange chromatography (e.g. as described in WO98 / 45247). Currently, the most widely used procedure for the purification of isoserinol 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. Often, the main distillation fraction contains isoserinol still contaminated by at least 0.5% w / w of serinol. Therefore, to obtain isoserinol with higher standards of purity suitable for the production of iodinated contrast agents, multiple film distillations are required, which lead to a sizeable impact on the retail price. The isoserinol commonly commercialized has a purity not higher than 98%-99%, which is considered unsatisfactory for the use in the preparation of X-ray contrast agents.

[0014] EP0470004 discloses a method for the purification of isoserinol that provides a highly purified isoserinol containing an amount of serinol impurity less than 0.3 % by weight, however it still achieves this result by using complex and expensive distillation procedures performed under vacuum (e.g. by using liquid-film or wiped-film evaporators).

[0015] For this reason, it is important to provide new straightforward and cost-effective methods for the selective purification of isoserinol from the above-mentioned impurities, particularly serinol.

[0016] In this respect, it has surprisingly been found that isoserinol can be easily separated and purified from serinol, through the selective formation of a zwitterionic adduct of the latter with a boronic acid in an aqueous environment. In fact, this reaction leads to the formation and selective precipitation of a serinol boronate ester as a solid, that can be then easily removed by filtration from the reaction mixture. The method of the invention thus represents an efficient and sustainable method of purification of isoserinol from the serinol formed as impurity during its synthesis. The filtrate containing isoserinol can be hydrolysed and processed, for instance through an ion exchange resin, to give pure isoserinol as desired, and the pure boronic acid that can be recycled for further purifications.

[0017] 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.

[0018] Summary of the invention

[0019] In a first aspect, the aim of the present invention is to provide an alternative process for the purification of 3-amino-l,2-propanediol (isoserinol) 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, since it involves the use of environmentally friendly solvents like water and allows to recycle and reuse the starting reagents.

[0020] Accordingly, the invention provides a simple and economic process for the removal of serinol from aqueous mixtures of crude isoserinol obtained from its manufacturing process with a suitable boronic acid.

[0021] Isoserinol is an essential starting material in the synthesis of several non-ionic X-ray contrast agents such as for instance lomeprol, lohexol, lodixanol, lopromide, loversol and the like. According to the invention, it can be obtained with an acceptable purity level, using a purification process for the removal of serinol impurity which is also easily applicable in 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 eliminated from the crude isoserinol by selective filtration of the precipitate.

[0022] This advantageously makes the purification process of the invention a straightforward, cheap and environmentally friendly method, which can conveniently replace, even in an industrial set up, the difficult and energetically demanding procedures currently in place and allows to remove serinol providing 3-amino-l,2-propanediol (isoserinol) 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 boronic ester of serinol and recycled in a subsequent purification step.

[0023] Moreover, the present invention further relates to the use of optionally substituted phenyl boronic acids for the purification of 3-amino-l,2-propanediol, a key reagent useful in the synthesis of different compounds, and in particular of non-ionic X-ray contrast agents like lomeprol and the like.

[0024] Detailed Description of the Invention

[0025] According to a first aspect, the present invention relates to a process for the purification of 3-amino-l,2-propanediol (isoserinol), or a base or salt thereof, in a mixture also including 2-amino-l,3-propanediol (serinol), said process comprising the following steps: a) reacting said mixture 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 intermediate of formula (II) wherein Ri and R2 are as defined above, formed by condensation of said boronic acid of formula (I) with serinol; b) separating said intermediate of formula (II) from the reacted mixture; and c) hydrolyzing the remaining solution to provide 3-amino-l,2-propanediol (isoserinol) purified from serinol and to optionally recover the boronic acid of formula (I).

[0026] In a preferred embodiment the reaction of step a) is carried out with a boronic acid of formula (I) wherein both groups Ri and R2 are hydrogen.

[0027] In another preferred embodiment Ri is hydrogen and R2 is selected from methyl, ethyl, propyl, tert-butyl, methoxy and chloro.

[0028] 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.

[0029] In a preferred embodiment the condensation of step a) is performed at a temperature comprised between 50 °C and 120 °C. More preferably, it is carried out at a temperature comprised between 70 °C and 110 °C or even more preferably between 80 °C and 100 °C. In the most preferred embodiment, the reaction of step a) is carried out at 90 °C.

[0030] Preferably, step a) is carried out in water, optionally in the presence of a base. For instance, the base can be selected from NaOH, KOH, Ca(OH)2, NaHCOs, KHCO3, NaCOs, CaCOs, K2CO3 and the like. More preferably, it is carried out in water in the presence of NaOH or K2CO3. In a preferred embodiment the molar ratio between the base and isoserinol is comprised between 0.3: 1 and 1: 1.

[0031] In another preferred embodiment, step a) is carried in water, with or without the presence of a base, in the presence of a suitable amount of a solvent. Preferably, said solvent is an alcohol selected from methanol, ethanol, propanol, 2-propanol, butanol, and the like. More preferably the solvent is 2-propanol.

[0032] 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).

[0033] In a preferred embodiment the molar ratio between the boronic acid of formula (I) and 3-amino-l,2-propanediol in step a) is comprised between 1 : 1 and 2: 1. Preferably it is 1: 1.

[0034] Preferably the intermediate of formula (II) formed in step a) is isolated by precipitation and collected by filtration of the mixture of step a).

[0035] The hydrolysis of step c) 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.

[0036] Optionally, in the process of the invention, step c) is followed by step d) relating to a further purification of the 3-amino-l,2-propanediol obtained from step c) through ion exchange chromatography.

[0037] The optional purification of step d) is preferably carried out by eluting the solution of 3-amino-l,2-propanediol obtained from step c) through a column packed with a suitable ion exchange resin. Preferably, after completion of the chromatography, the purified 3- amino-l,2-propanediol is recovered by adding a base, such as for instance aqueous ammonia.

[0038] Optionally, the purification of step d) through ion exchange chromatography can be preceded by the elution of the solution of 3-amino-l,2-propanediol obtained from step c) through a suitable scavenger resin (step i), to remove any possible residual of boronic acid. According to these latter embodiments, the invention relates to a process for the purification of 3-amino-l,2-propanediol (isoserinol), or a base or salt thereof, in a mixture also including 2-amino-l,3-propanediol (serinol), said process comprising the following steps: a) reacting said mixture 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 intermediate of formula (II) wherein Ri and R.2 are as defined above, formed by condensation of said boronic acid of formula (I) with serinol; b) separating said the intermediate of formula (II) from the reacted mixture; c) hydrolyzing the remaining solution to provide a solution of 3-amino-l,2-propanediol (isoserinol) purified from serinol and to optionally recover the boronic acid of formula (i); and optionally i) eluting said solution of purified 3-amino-l,2-propanediol through a scavenger resin; and / or d) purifying the 3-amino-l,2-propanediol obtained from step c) or i) through ion exchange chromatography.

[0039] In another aspect, the present invention relates to a process as described above wherein the boronic acid of formula (I) is recovered from step c) and recycled in the reaction of step a). Such reagent can be recovered as solid by filtrating the acidic mixture obtained from the hydrolysis of step c). The boronic acid of formula (I) thus recovered can be re-used as such or purified before the recycling in a subsequent reaction batch.

[0040] A further aspect of the present invention relates to the use of the pure isoserinol, obtained as described above, for the preparation of a non-ionic X-ray contrast agent from a mixture also including 2-amino-l,3-propanediol by means of the formation of the intermediate of formula (II) as defined above and removal of said intermediate from said mixture.

[0041] Moreover, the invention generally relates to the use of the boronic acid of formula (I) as defined above for the purification of 3-amino-l,2-propanediol.

[0042] The process of the present invention also encompasses hydrates, solvates, organic or mineral salts of the compounds described above, particularly of 3-amino-l,2-propanediol, the boronic acids of formula (I) and the zwitterionic adduct of formula (II).

[0043] 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.

[0044] The term "Ci-Ce alkoxy" refers to an alkoxyl group comprising a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Preferably the methoxy group is used.

[0045] 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.

[0046] 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.

[0047] According to the invention, the reaction 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 isoserinol is comprised between 0.3: 1 and 1: 1.

[0048] Preferably, the base is added in stoichiometric amount (1: 1) and the molar ratio among the crude isoserinol, the boronic acid and the base is 1: 1 : 1. Adding the base can be useful to reduce the acidity of the solution due to the boronic acid and to keep it at pH preferably comprised between 5 and 9, more preferably between 6 and 8.

[0049] During the reaction step a), the condensation product of formula (II), i.e. corresponding to the condensation product formed between serinol and the boronic acid, tends to selectively precipitate so that it can be separated by filtration from the rest of the mixture (step b). Conversely, it was surprisingly found that isoserinol, despite being a isomer of serinol, with similar chemical structure, does not form a precipitate when reacting with a boronic acid, remaining dissolved in the aqueous mixture.

[0050] The 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.

[0051] To foster such precipitation and accelerate the reaction time, a low 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 the base as described above) 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 and speed up the precipitation of serinol boronate ester. Preferably in step a) the molar ratio between 3-amino-l,2-propanediol and the boronic acid of formula (I) is stoichiometric and corresponding to at least 1 : 1. More preferably, the amounts of boronic acid equivalents is at least equal to the total amount of equivalents of the aminoalcohol species present in the mixture, including serinol and other impurities.

[0052] According to step c) of the invention, the remaining solution can be hydrolyzed according to standard methods, preferably in acidic conditions. For instance, hydrolysis can be performed with an acid selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonic acid, and heating the mixture to a temperature comprised between 20 and 70 °C for a time comprised between 5 and 30 minutes. Preferably, the 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).

[0053] To obtain a quantitative recovery of the boronic acid of formula (I), the 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 in fact can possibly lead to degradation of the boronic acid with formation of boric acid and the corresponding benzene derivative.

[0054] After the hydrolysis of step c), the solid comprising the recovered boronic acid of formula (I) can be separated from the liquid mixture comprising 3-amino-l,2-propanediol. For instance, this can be accomplished by filtering the solid under reduced pressure. The remaining liquid mixture can be then evaporated under reduced pressure to recover isoserinol or a salt thereof.

[0055] To obtain the purified isoserinol 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.

[0056] 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 d) can be preceded by an optional further purification through a suitable scavenger resin, that is specifically 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™ CR.B03 or / V' / V-diethanolaminomethyl polystyrene or other equivalent commercial resins can be conveniently selected, based on the common knowledge on this matter.

[0057] 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.

[0058] In step d) the solution obtained from step c) 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.

[0059] Once the elution is completed, isoserinol 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 isoserinol purified from serinol by-product.

[0060] The recovery of the solid boronic acid of formula (I) can be carried out simply by filtration after the hydrolysis step c), as it precipitates during or at the end of the hydrolysis. If necessary, the recovered boronic acid of formula (I) can be purified prior to be recycled in a subsequent batch according to known methods.

[0061] 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.

[0062] 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.

[0063] The process of the invention can be performed using different boronic acids and different conditions. The following examples illustrate some preferred and representative conditions to carry out the invention disclosed herein.

[0064] Experimental part

[0065] All the starting materials mentioned above are commercially available or were purchased from Sigma-Aldrich and TCI Europe.

[0066] In the following examples crude isoserinol was prepared following the procedure described in EP0470004, i.e. by reaction of glycidol with ammonia.

[0067] Analytical Methods

[0068] 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):

[0069] 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:

[0070] GC Column: Agilent J&W HP-5MS Ultra Inert, 30 m x 0.25 mm, 0.25 pm

[0071] Injection volume: 1 pL

[0072] Inlet mode: split (split ratio 20: 1)

[0073] Solvent delay: 1 min

[0074] 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.

[0075] All percentages are by weight unless otherwise indicated.

[0076] Example 1

[0077] Purification of isoserinol by reaction with phenylboronic acid in water

[0078] A 95:5 mixture of isoserinol (25.11 g, 0.276 mol) and serinol (1.35 g, 0.015 mol) was dissolved in 290 mL of deionized water under magnetic stirring, then phenylboronic acid (35.41 g, 0.290 mol) was added. The solution was refluxed at 90 °C for 4 hours. Upon cooling, a liquid yellowish layer separated. The volume of the reaction mixture was reduced by vacuum distillation at 60 °C at about 250 mL obtaining a homogeneous solution. Upon cooling at 10 °C, a white precipitate was formed and isolated by suction filtration. After drying overnight in a vacuum oven, the solid was characterized by NMR and identified as a mixture of phenylboronic acid serinol ester (2.9 g, 0.014 mol) and unreacted phenylboronic acid (0.25 g, 0.002 mol).

[0079] The filtrate was acidified with 63 mL of 20 % w / w HCI to give 30 g of phenylboronic acid which was filtered (recovery yield: 85.7%).

[0080] The filtered solution was eluted through a column packed with 150 g of an Amberlite S-900 hydroxy resin. The column was further eluted with 1 L of deionized water and the combined eluted fractions were evaporated to dryness to give 25 g of a viscous oil identified as isoserinol (GC-MS purity: 99.7 %). Yield: 99.6%

[0081] Example 2

[0082] Purification of isoserinol by reaction with phenylboronic acid in water and a base

[0083] A 50:50 mixture of isoserinol (4.55 g, 50 mmol) and serinol (4.55 g, 50 mmol) was dissolved in 200 mL of deionized water under magnetic stirring, then phenylboronic acid (12.2 g, 100 mmol) and NaOH (4.00 g, 100 mm) were added. The mixture was heated to 90 °C for 24 hours. Upon cooling, the formation of a white precipitate was observed. After 5 days it was isolated by suction filtration. After characterization by NMR it was identified as the phenylboronic acid serinol ester (10.24 g, 49 mmol; conversion Yield: 98%). The remaining filtered solution was evaporated to dryness obtaining 9.36 g of a viscous oil.

[0084] Comparative Example Condensation of isoserinol with phenylboronic acid

[0085] Isoserinol (9.10 g, 100 mmol) was dissolved in 200 mL of deionized water under magnetic stirring and phenylboronic acid (12.2 g, 100 mmol) and NaOH (4.00 g, 100 mmol) were added. The reaction was heated to 90 °C for 24 hours. Then, the mixture was brought to room temperature. After 8 days, slight white solid precipitation was observed, corresponding to unreacted phenylboronic acid, while isoserinol did not form a precipitate.

[0086] Analogous experiments in the absence of the base or with different solvents yielded no different results.

[0087] References

[0088] 1. A. Gallotti et al., Eur. J. Radiol. 1994, 18(S1), S1-S12

[0089] 2. WOOO / 32561

[0090] 3. EP2673258

[0091] 4. US4,360,697

[0092] 5. WO98 / 45247

[0093] 6. EP0470004

[0094] 7. US4,503,252

[0095] 8. Musu C. et al, Journal of Chromatography A (1988), 449, 432-439

Claims

CLAIMS1. A process for the purification of 3-amino-l,2-propanediol (isoserinol), or a base or salt thereof, in a mixture also including 2-amino-l,3-propanediol (serinol), said process comprising the following steps: a) reacting 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 R.2 are as defined above, formed by condensation of said boronic acid of formula (I) with serinol; b) separating said intermediate of formula (II) from the reacted mixture; and c) hydrolyzing the remaining solution to provide 3-amino-l,2-propanediol (isoserinol) purified from serinol and to optionally recover the boronic acid of formula (I).

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 in water.

6. 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.

7. The process according to claim 5 or 6, wherein step a) is carried out in water in the presence of a solvent selected from methanol, ethanol, propanol, 2-propanol and butanol.

8. The process according to claim 7 wherein the amount of solvent is comprised between 1% and 20% v / v.

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

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

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

13. The process according to claim 1, for the purification of 3-amino-l,2-propanediol (isoserinol) in a mixture also including 2-amino-l,3-propanediol (serinol), comprising : a) reacting said mixture 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 intermediates of formula (II)wherein Ri and R.2 are as defined above, formed by condensation of said boronic acid of formula (I) with serinol; b) separating said intermediate of formula (II) from the reacted mixture; c) hydrolyzing the remaining solution to provide a solution of 3-amino-l,2- propanediol (isoserinol) purified from serinol and to optionally recover the boronic acid of formula (I); and optionally i) eluting said solution of purified 3-amino-l,2-propanediol through a scavenger resin; and / or d) purifying the 3-amino-l,2-propanediol obtained from step c) or i) through ion exchange chromatography.

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

15. Use of a boronic acid of formula (I) as defined in claim 1 for the purification of3-amino-l,2-propanediol from a mixture also including 2-amino-l,3-propanediol by means of the formation of the intermediate of formula (II) as defined above and removal of said intermediate from said mixture.

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