Method for the diastereoselective synthesis of DL-2,5-dihydroxyadipic acid

Abstract

The present patent application concerns a method for the diastereoselective synthesis of DL-2,5-dihydroxyadipic acid (DL-DHAA) of formula (I) (I) comprising the catalytic hydrogenation step of 3 -hydroxy -pyran-2-one-6-carboxylic acid (GABOH) of formula (II); (II) wherein the catalytic hydrogenation step is conducted at room temperature and using H2 at atmospheric pressure in a protic or aprotic polar organic solvent or in water, and, when the catalytic hydrogenation step is conducted in a protic or aprotic polar organic solvent, the method comprises a hydrolysis step in water subsequent to the catalytic hydrogenation step. A further object of the present patent application is a method for the synthesis of the dilactone DL-2,5-dioxabicyclo [2.2.2] ottano-3, 6-dione (DL-GabDil) of formula (VI) comprising a thermal dehydration step of DL-DHAA obtained according to the method object of the present application reported above. (VI)

Description

[0001] TITLE: "Method for the diastereoselective synthesis of DL-2,5-dihydroxyadipic acid’'’

[0002] DESCRIPTION FIELD OF THE INVENTION

[0003] The present invention is in the technical field of the synthesis of 2,5-dihydroxyadipic acid (D,L-DHAA), by means of a diastereoselective catalytic hydrogenation reaction under mild conditions and with high yields, which provides predominantly the racemic compound DL-DHAA starting from reagents obtained from renewable sources, which can be exploited for the preparation of the dilactone DL-2,5-dioxabicyclo[2.2.2]octane-3, 6-dione.

[0004] STATE OF THE ART

[0005] The 2,5-dihydroxyadipic acid (DHAA, formula (la)) is an a, a'-dihydroxy dicarboxylic acid and is the a,a'-dihydroxylated derivative of adipic acid, an important monomer used in the synthesis of polymers such as nylons, polyesters and polyurethanes.

[0006] OH

[0007]

[0008] OH

[0009] Formula (la)

[0010] DHAA exists in two diastereoisomeric forms: the racemic form DL-DHAA, given by the mixture of two optically active enantiomers (IUPAC names: (2R,5R)-2,5-dihydroxyhexanedioic acid and (2S,5S)-2,5-dihydroxyhexanedioic acid, formula (I)), and the optically inactive meso-DHAA form (IUPAC name: (2R,5S)-2,5-dihydroxyhexanedioic acid, formula (lb)).

[0011]

[0012] Formula (I)

[0013]

[0014] OH O

[0015] Formula (lb)

[0016] DHAA itself is interesting as a functional building block for polymeric structures, also obtainable from renewable sources; in fact, it is usable in the synthesis of polymers with new and improved properties, which are biodegradable and obtained from reagents of biological origin.

[0017] Furthermore, only the racemic form DL-DHAA can undergo thermal dehydration and form the dilactone DL-2,5-dioxabicyclo[2.2.2]octane-3, 6-dione or DL-GabDil (formula (VI)).

[0018]

[0019] Formula (VI)

[0020] The latter can be used as a comonomer in biodegradable polymers such as the polylactic acid or PLA in order to improve their rheological properties by acting as a branching agent.

[0021] Problem of the known art

[0022] The methods for the synthesis of DHAA described in the known art allow it to be obtained only as a mixture of diastereoisomers and only in some cases starting from renewable sources. In the documents in which the synthesis of the DHAA is described by means of a catalytic hydrogenation step, the conditions used provide for high hydrogen pressures and, often, high temperatures. As a direct consequence of this, a synthetic eco-compatible pathway is absent in the state of the art which, starting from renewable sources, allows the dilactone DL-GabDil, which can be synthesized only from the DL-DHAA diastereoisomer, to be obtained in high yields.

[0023] Historically, the synthesis provided for the preparation of the mixture of the two diastereoisomers of the DHAA starting from adipic acid through the dibromoderivative intermediate. In the synthesis described by H. R. Le Sueur in 1908 in “The action of heat on a-hydroxy carboxylic acids. Part IV. Racemic a, a’ -dihydroxyadipic acid and meso- a,a'-dihydroxyadipic acid” (J. Chem. Soc., Trans. 1908, 93, 716-7251), the adipic acid, obtained from the oxidation of cyclohexanone with potassium permanganate in an alkaline solution, is converted into the corresponding acyl chloride by means of PC15; treating the product with bromine gives the dibromo derivative. The addition of sodium hydroxide and, subsequently, of copper sulfate and hydrogen sulfide allow the DHAAto be obtained as a mixture of diastereoisomers, separable by crystallization. The melting points of the two diastereoisomers were found to be 146 °C for the racemic isomer and 174 °C for the meso form.

[0024] K. Freudenberg et al. (Justus Liebigs Annalen der Chemie, 1934, Volume 510, Issue 1, pp. 206-222) report the non-diastereoselective synthesis of 2-methyl-2,5-dihydroxyadipic acid and of the relative dilactone.

[0025] W. D. Albert et al. in “The Action of Barium Hydroxide on Certain of the Monobasic Sugar Acids" (J. Am. Chem. Soc. 1935, 57, 133-134) have shown how, by treating salts of monobasic acids derived from sugars with an aqueous solution of barium hydroxide at 140 °C, the salt of meso-DHAA is obtained together with other decomposition co-products.

[0026] Alternatively, more recently, A. Dewaele et al. in “Synthesis of Novel Renewable Polyesters and Polyamides with Olefin Metathesis” (ACS Sust. Chem. Eng. 2016, 4, 5943-5952) describe the preparation of DHAA starting from methyl vinyl glycolate (MVG) derived from sugars from biomass: the MVG undergoes a metathesis reaction and subsequent hydrolysis leading to the formation of 2,5-dihydroxy-3-hexenedioic acid which, upon hydrogenation with H2 at 20 bar and 5 wt% Pd / C at 25 °C, provides DHAA with a melting point of 174 °C, and therefore identifiable as the meso form according to what was previously reported by H. R. Le Sueur.

[0027] CN111233657 discloses a method for the synthesis of DHAA by catalytic hydrogenation of aldaric acids. The conditions provide for a pressure from 1 to 4 MPa of H2 and temperatures between 110 °C and 180 °C in water and in the presence of a catalyst comprising Pd, Pt, Ru, Rh or Ir supported on a support comprising silicon oxide, zirconium oxide, titanium dioxide and cerium oxide. In addition to consideringrather drastic conditions, the product is once again the mixture of the two diastereoisomeric forms of the DHAA.

[0028] An alternative synthetic method, which provides for the oxidation of 1, 2,5,6-hexanetetrol in water with Pt(Bi) as a catalyst with an excess of NaOH at 150°C for 16 hours, is described in WO2019199468; the two diastereoisomers of DHAA represent the main product.

[0029] The same article by H.R. Le Sueur previously cited with reference to the synthesis of the DHAA also describes the synthesis of the dilactone DL-GabDil by heating to 160-170°C and at a pressure of 26.7-40 mbar starting from the DL-DHAA isolated by crystallization. The dilactone product is recovered as a crystalline sublimate. Instead, the heating of the meso-DHAAto 180-190 °C at a pressure of 46.7-53.3 mbar leads to the formation of a hard, glassy substance, which does not melt up to 250 °C, the temperature at which it decomposes, identified as the lactone-lactide of the meso-DHAA.

[0030] Instead, Kostyanovsky et al. in “Autoassembly of cage structures 9. Complete autoassembly of dilactones of a, a'-dihydroxy-a, a’ -dialkoxy carbonyladipic and -pimelic acids” (Russ. Chem. Bull, 1995, 44, 318-321) describe obtaining the dilactone (DL-GabDil) by refluxing a mixture of tetraethyl-l,2-ethylene-bistartronate with an excess of para-toluenesulfonic acid (4 moles per mole of substrate) in toluene for 48 hours. At the end of the reaction, the excess of para-toluenesulfonic acid is filtered off, the solution is concentrated, extracted with chloroform and reconcentrated. The residue is washed with ethyl ether and sublimated (120°C, 1.33 mbar) to obtain the dicarboxylate dilactone with a yield of 33%. The black residue obtained after extraction with chloroform is anhydrified and sublimated at 90°C (4 mbar) to give the dilactone DL-GabDil with a yield of 20%.

[0031] Finally, W02002100921 describes the preparation of the DL-GabDil to be used as a monomer in L-lactate-based copolymers. In fact, the use of bicyclic diesters allows for the introduction of monomeric units capable of giving rise to branching following the ring-opening reaction, with a consequent modulation of the rheological properties of the polymer. The preparation of the dilactone occurs starting from a, a' -dibromoadipic acid (100 parts), Na2CO3 as a base (35 parts) in acetonitrile (800 parts) at reflux for 7hours. The work-up of the mixture leads to obtaining the dilactone (20 parts) which is subsequently sublimated at 90°C and 1.33-2 mbar.

[0032] SUMMARY OF THE INVENTION

[0033] Therefore, the need arises for a simple, eco-compatible and diastereoselective process for the synthesis of DL-DHAA in view of its potential as such and / or as a precursor of the dilactone DL-GabDil, which is easily obtainable therefrom.

[0034] The object of the invention is a method for the diastereoselective synthesis of DL-2,5-dihydroxyadipic acid comprising the catalytic hydrogenation step of 3 -hydroxy -pyran-2-one-6-carboxylic acid (GABOH), wherein the catalytic hydrogenation step is carried out at room temperature and using H2 at atmospheric pressure in a protic or aprotic polar organic solvent or in water, and when the catalytic hydrogenation step is carried out in a protic or aprotic polar organic solvent, the method comprises a hydrolysis step in water subsequent to the catalytic hydrogenation step.

[0035] A further object of the present patent application is a method for the synthesis of the dilactone DL-2,5-dioxabicyclo[2.2.2]octane-3, 6-dione (DL-GabDil) comprising a thermal dehydration step of DL-DHAA obtained according to the method object of the present application reported above.

[0036] Advantages of the invention

[0037] The invention consists of a method for the diastereoselective synthesis of the DL-DHAA starting from GABOH (formula (II)) by means of catalytic hydrogenation, which allows the use of mild conditions and at the same time guarantees excellent diastereoselectivity and high yields.

[0038]

[0039] OH

[0040] Formula (II)

[0041] Furthermore, this method is optimal for producing DL-DHAA to be used in the synthesis of the dilactone DL-GabDil, obtainable only from the DL-DHAA diastereoisomer. Only by using the latter obtained according to the method object ofthe present invention, it is possible to obtain DL-GabDil in high yields with respect to the initial quantity of GABOH, as non-diastereoselective syntheses of the DHAAlead to the production of meso-DHAA, which cannot be exploited for obtaining DL-GabDil.

[0042] Advantageously, the method object of the present invention allows the use of starting substrates obtained from renewable sources, such as GABOH, which is easily obtainable from aldaric acids.

[0043] Also advantageously, the use of hydrogen at atmospheric pressure, room temperature and, possibly, in the presence of solvents that are not problematic in terms of safety and respect for the environment, such as for example ethanol, make the method particularly eco-sustainable.

[0044] Always advantageously, the synthesis method object of the present invention is highly diastereoselective and allows to selectively obtain DL-DHAA, which can in turn be exploited in the synthesis at high yields of its dilactonic derivative DL-GabDil.

[0045] Advantageously, both DL-DHAA and DL-GabDil can be exploited for obtaining copolymers, preferably biocompatible copolymers such as copolymers with poly lactic acid (PLA), with optimal rheological properties.

[0046] Finally, in particular, the dilactone DL-GabDil can react with diamines, producing polyamides under mild conditions, as shown in Example 8.

[0047] DESCRIPTION OF THE FIGURES

[0048] In the reaction schemes and in the formulas reported in the figures, DL-DHAA and its derivatives (DL-DHAA monolactone, DL-GabDil, DL-DHAA monoester and DL-DHAA diester) are indicated only by means of one of the two enantiomers constituting the racemes, specifically the (2R,5R)-2,5-dihydroxyadipic acid enantiomer and its derivatives. However, the reactions involving these compounds provide for the further presence of their enantiomer, always in a 1 : 1 ratio to the represented enantiomer, which has been omitted for simplicity of representation.

[0049] Figures la), lb), 1c) and Id) respectively represent the reaction scheme of the catalytic hydrogenation step conducted in water; acetic acid, tetrahydrofuran and ethanol.Figure 2a) represents the reaction scheme of the hydrolysis step of the products obtained from the catalytic hydrogenation step in tetrahydrofuran; figure 2b) represents the reaction scheme of the synthesis of DL-GabDil by thermal dehydration of the DL-DHAA in acetic acid; figure 2c) represents the reaction scheme of the hydrolysis of the DL-GabDil to give DL-DHAA.

[0050] Figures 3a), 3d) and 3g) report the 13C NMR spectrum in D2O of the products of the catalytic hydrogenation reactions in water; figures 3b), 3e) and 3h) report the 13C NMR spectrum in D2O of the products of the catalytic hydrogenation reactions in tetrahydrofuran followed by hydrolysis; figures 3c), 3f) and 3i) report the 13C NMR spectrum in D2O of the products of the hydrolysis reactions of the DL-GabDil. In figures 3a), 3b) and 3c) the expansion of the 13C NMR spectra from 178.0 ppm to 177.1 ppm is displayed; in figures 3d), 3e) and 3f) the expansion of the 13C NMR spectra from 70.0 ppm to 69.3 ppm is displayed; in figures 3d), 3e) and 3f) the expansion of the 13C NMR spectra from 29.4 ppm to 28.6 ppm is displayed.

[0051] Figure 4a) represents the1H NMR spectrum in DMSO-d6 of the product obtained from the catalytic hydrogenation step conducted in water; figure 4b) is the ATR-FTIR spectrum of the same product.

[0052] Figure 5a) represents the 'H NMR spectrum in DMSO-d6 of the mixture of products obtained from the catalytic hydrogenation step conducted in acetic acid by evaporation of the solvent in the cold; figure 5b) is the 1H NMR spectrum in DMSO-d6 of the same mixture of products obtained from the catalytic hydrogenation step conducted in acetic acid by evaporation of the solvent under heat.

[0053] Figure 6 represents the 'H NMR spectrum in DMSO-d6 of the mixture of products obtained from the catalytic hydrogenation step conducted in tetrahydrofuran.

[0054] Figure 7 represents the 'H NMR spectrum in DMSO-d6 of the mixture of products obtained from the catalytic hydrogenation step conducted in ethanol.

[0055] Figure 8 represents the 'H NMR spectrum in DMSO-d6 of the product obtained from the hydrolysis step subsequent to the catalytic hydrogenation step conducted in tetrahydrofuran. The peak at about 8 ppm is relative to the terephthalic acid (TPA) standard.Figure 9a) represents the 'H NMR spectrum in CDC13 of the DL-GabDil; figure 9b) represents the13C NMR spectrum in CDC13 of the DL-GabDil.

[0056] Figure 10a) represents the MS / MS ESImass spectrum of the DL-GabDil; figure 10b) represents the ATR-FTIR spectrum of the DL-GabDil.

[0057] Figure Ila) represents the 'H NMR spectrum in D2O of the product obtained from the hydrolysis of the DL-GabDil; figure 11b) represents the13C NMR spectrum in D2O of the same product.

[0058] DETAILED DESCRIPTION OF THE INVENTION

[0059] For the purposes of the present invention, the definition “comprising” does not exclude the presence of further components / steps, in addition to those expressly listed after this definition.

[0060] For the purposes of the present invention, the definitions “consisting of’ or “constituted by” instead exclude the presence of components / steps not expressly listed. By diastereoisomeric ratio is meant the ratio that exists between two diastereoisomers, possibly expressible as a percentage as the percentage ratio between the quantity of one diastereoisomer and the sum of the quantities of both diastereoisomers.

[0061] By diastereoselective reaction or synthesis is meant a reaction or synthesis capable of preferably producing one of the two diastereoisomers, thus providing a diastereoisomeric mixture with a diastereoisomeric ratio different from 50:50, or from 50% as a percentage.

[0062] By diastereoselectivity of a diastereoselective reaction is meant the percentage diastereoisomeric ratio referred to the diastereoisomer of interest produced by means of said diastereoselective reaction.

[0063] By reaction yield, expressed in percentage terms, is meant the molar percentage ratio of the product obtained over the total moles of the reagent.

[0064] By DHAA is meant the diastereoisomeric mixture given by DL-DHAA and meso-DHAA.

[0065] By room temperature is meant a temperature comprised between 15 °C and 30 °C, preferably between 20 °C and 25 °C.The synthesis method object of the present invention comprises the catalytic hydrogenation step of the GABOH substrate, which is conducted at room temperature and using gaseous hydrogen at atmospheric pressure to obtain DL-DHAA with high diastereoselectivity. Said step can be conducted in aprotic polar organic solvents, protic polar organic solvents or in water.

[0066] Preferably, the aprotic polar organic solvent is a cyclic or alkyl ether, more preferably it is tetrahydrofuran (THF).

[0067] Preferably, the protic polar organic solvent is a C2-C5 alcoholic solvent, preferably ethanol or a C2-C5 monocarboxylic acid, preferably acetic acid.

[0068] Preferably, the catalyst of the catalytic hydrogenation step comprises a noble metal and a support material in a weight ratio comprised between 2% and 10%, more preferably 5% of the total weight of the noble metal and the support material.

[0069] Preferably, the catalyst of the catalytic hydrogenation step is Pd / C.

[0070] Preferably, GABOH is obtained from aldaric acids from renewable sources, according to a procedure disclosed by Leonard! et al. in “Pyrone Synthesis from Renewable Sources: Easy Preparation of 3 -Acetoxy -2-oxo-2H-pyran-6-carboxylic Salts and their Derivatives as 3-Hydroxy-2H-pyran-2-one from C6 Aldaric Acids” (Eur. J. Org. Chem., 2020: 241-251).

[0071] Preferably, when the solvent is water, the main product of the catalytic hydrogenation step comprises DL-DHAA, with a diastereoselectivity comprised between 51% and 80%, more preferably comprised between 60% and 66%, according to the synthesis scheme shown below and in figure la).

[0072] o OH O OH O OH H?. H?O A , i’d / C {!>%) HO j Msso-2.5 rfiirfrossiarfipic

[0073]

[0074] DL-2.5-diidfSS^3di»)C{DL-DHAA} (Mese-DMAA)

[0075] Preferably, when the solvent is water, the weight ratio between GABOH and catalyst is comprised between 1:0.1 and 1:1, more preferably it is 1:0.5.

[0076] Preferably, when the solvent is water, the weight ratio between GABOH and water is comprised between 1:10 and 1:100, preferably it is 1:20.Preferably, when the solvent is water, the reaction time of the catalytic hydrogenation step is comprised between 12 hours and 24 hours, preferably it is 23 hours.

[0077] According to a preferred alternative, when the solvent is water, the yield in DHAA of the catalytic hydrogenation step is comprised between 85 and 99% and the purity of the DHAA product is comprised between 92% and 99%.

[0078] Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, or a C2-C5 monocarboxylic acid, preferably acetic acid, the products of the catalytic hydrogenation step comprise DL-DHAA monolactone as the main product and DL-DHAA and DL-GabDil as possible secondary products, according to the synthesis scheme shown below and in figures lb) and 1c).

[0079]

[0080] Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, or a C2-C5 monocarboxylic acid, preferably acetic acid, the yield of the DL-DHAA monolactone is comprised between 50% and 90%, the yield of the DL-DHAA is less than 20% and the yield of the DL-GabDil is less than 20%.

[0081] Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, the weight ratio between GABOH and catalyst is comprised between 1:0.05 and 1:0.75, more preferably it is 1:0.5.

[0082] Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, the weight ratio between GABOH and solvent is comprised between 1:10 and 1:100, preferably it is 1:26.5.

[0083] Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, the reaction time of the catalytic hydrogenation step is comprised between 12 hours and 24 hours, preferably it is 23 hours.According to a preferred alternative, when the solvent is a C2-C5 monocarboxylic acid, preferably acetic acid, the weight ratio between GABOH and catalyst is comprised between 1:0.05 and 1:0.5, more preferably it is 1:0.25.

[0084] Preferably, when the solvent is a C2-C5 monocarboxylic acid, preferably acetic acid, the weight ratio between GABOH and solvent is comprised between 1:10 and 1:100, preferably it is 1:20.6.

[0085] Preferably, when the solvent is a C2-C5 monocarboxylic acid, preferably acetic acid, the reaction time of the catalytic hydrogenation step is comprised between 24 hours and 48 hours, preferably it is 45 hours.

[0086] According to a further preferred alternative, when the solvent is a C2-C5 alcoholic solvent, preferably ethanol, the main products of the catalytic hydrogenation step comprise DL-DHAAmono- and diester, more preferably DL-DHAA ethyl mono- and diester, according to the synthesis scheme shown below and in figure Id).

[0087] o OH O Oi-:nI ItJ| A ,o, ....^ X ,.-x X, ,oxV' ■' O ’ 'O Pa’C <5%} 'O' y If

[0088]

[0089] 0 OH O OH 6

[0090] Preferably, when the solvent is ethanol, the yield of the DL-DHAA ethyl monoester is comprised between 70% and 99%, more preferably it is 80%, and the yield of the DL-DHAA ethyl diester is comprised between 1% and 30%, more preferably it is 20% Preferably, when the solvent is a C2-C5 alcoholic solvent, preferably ethanol, the weight ratio between GABOH and catalyst is comprised between 1:0.05 and 1:0.5, more preferably it is 1:0.25.

[0091] Preferably, when the solvent is a C2-C5 alcoholic solvent, preferably ethanol, the weight ratio between GABOH and solvent is comprised between 1:10 and 1:100, preferably it is 1:16.

[0092] Preferably, when the solvent is a C2-C5alcoholic solvent, preferably ethanol, the reaction time of the catalytic hydrogenation step is comprised between 8 hours and 12 hours, preferably it is 9 hours.Preferably, when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, or when the solvent is a C2-C5 alcoholic solvent, preferably ethanol, the hydrogen used is free of moisture.

[0093] When the catalytic hydrogenation step is conducted in a protic or aprotic polar organic solvent, the method object of the present invention also comprises a hydrolysis step subsequent to the catalytic hydrogenation step, in which the products from the latter step are placed under stirring in water at a temperature comprised between 60 °C and 90 °C, preferably 90 °C, for a time comprised between 2 hours and 6 hours, preferably 4 hours, according to the synthesis scheme shown below and in figure 2a).

[0094]

[0095] Preferably, when the catalytic hydrogenation step is conducted in a protic or aprotic polar organic solvent, the hydrolysis step leads to obtaining DL-DHAA with a yield in DL-DHAA with respect to GABOH comprised between 85% and 99%, preferably between 90% and 96% and with a diastereoselectivity referred to DL-DHAA comprised between 90% and 99%, preferably comprised between 93% and 95%, as shown in table 1.

[0096] Solvent of the catalytic Diastereoselectivity DL- Yield in DL-DHAA (%)

[0097] hydrogenation step DHAA (%)

[0098] Tetrahydrofuran 95 93

[0099] Acetic acid 96 95

[0100] Ethanol 90 95

[0101]

[0102] Table 1

[0103] A further object of the present invention is a method for the synthesis of the dilactone DL-GabDil comprising the following steps:

[0104] a) synthesizing DL-DHAA according to any of the alternatives described above; and b) thermally dehydrating the DL-DHAA synthesized in step a), obtaining DL-GabDil.Preferably, the synthesis scheme of DL-GabDil is that shown below and in figure 2b).

[0105] p OH |

[0106] ,X .OH > AcOH 1 1

[0107]

[0108] Preferably, the thermal dehydration step takes place in a protic polar organic solvent, more preferably a C2-C5 monocarboxylic acid, even more preferably acetic acid. Preferably, the thermal dehydration step takes place by a mode comprising the use of said protic polar organic solvent chosen from: dehydration in an autoclave at a temperature comprised between 110°C and 140°C, preferably 140 °C and preferably at pressures comprised between 1 and 2 bar; dehydration with partial distillation of the solvent; dehydration with solvent at reflux with subsequent partial distillation of the solvent.

[0109] According to these modes, it is possible to obtain good yields of DL-GabDil, as the water formed during the dehydration process is removed.

[0110] Preferably, the DL-GabDil produced by the thermal dehydration step can be purified by crystallization and / or sublimation.

[0111] Preferably, the sublimation is conducted in a sublimation apparatus at a pressure of 0.4 mbar, placed in an oil bath at a temperature comprised between 100 °C and 160 °C, preferably 140 °C.

[0112] Alternatively to the use of a solvent in the thermal dehydration step, said step can preferably take place dry, i.e. in the absence of solvent, by placing the DL-DHAA dry in the sublimation apparatus and operating under the same conditions reported above for purification by sublimation.

[0113] Advantageously, the product formed by the dry mode is recovered already purified by sublimation.

[0114] Figure 3 reports 13C NMR spectra demonstrating the diastereoselectivity of the synthesis method object of the present invention. DL-GabDil can be hydrolyzed to form DL-DHAA again; preferably, this reaction is conducted by placing the DL-GabDil in water under stirring for 24 hours at a temperature of 40 °C, according to the synthesis scheme shown in figure 2c).

[0115] OH

[0116] H;.O

[0117] 40°C

[0118]

[0119] The blocked stereochemistry of the dilactone ensures that this reaction provides only the racemic form of 2,5-dihydroxyadipic acid, whose13C NMR spectra can be compared with the products of the catalytic hydrogenation reactions and subsequent hydrolysis to derive the diastereoselectivity of these methods.

[0120] EXAMPLES

[0121] Example 1: Catalytic hydrogenation of GA P> 11 in water

[0122]

[0123] (Meso-DHAA)

[0124] In a three-necked flask, 1.00 g of GABOH (97.8% purity, 6.27 mmol) was weighed and dispersed in 20 mL of deionized water. 0.50 g of 5% Pd / C (50% moisture) were added to the suspension, and the reaction was conducted at 24 °C, under stirring in a hydrogen atmosphere until no further hydrogen consumption was observed. After 24 hours, 330 mL of H2 (13.55 mmol) were consumed. The reaction mixture was filtered and the solvent was removed by distillation via rotavapor and dried with a mechanical pump. A white solid of 1.04 g was recovered. The solid was analyzed by 1H NMR analysis, using terephthalic acid as standard (figure 4a)), and ATR-FTIR analysis (figure 4b)). The white solid resulted to be 2,5-dihydroxyadipic acid (DHAA) with a purity of 94.21% and a yield of 84.54%. The reaction was repeated four times, obtaining a yield in DHAA comprised between 85% and 93% and a purity of the DHAA comprised between 94% and 96%.

[0125] Example 2: Catalytic hydrogenation of GABOH in acetic acid

[0126] Hj. AcOM F»«C {5% ■

[0127]

[0128] In a flask, 0.50 g of 5% Pd / C (50% moisture) were weighed and dispersed in 10 mL of acetic acid and 1 mL of acetic anhydride for 1 hour. After this time, the suspension was decanted and the liquid was removed. In a three-necked flask, 1.01 g of GABOH acid (97.8% purity, 6.33 mmol) were weighed and dispersed in 15 mL of acetic acid. The Pd / C treated as described above was dispersed in 5 mL of acetic acid and added to the suspension; the reaction was conducted under stirring at room temperature in a hydrogen atmosphere until no further hydrogen consumption was observed. After 45 hours, 390 mL of H2 (16.06 mmol) were consumed. The reaction mixture was filtered and the solvent was removed in the cold by a stream of air from a small part of the crude (0.3 mL), obtaining a solid which was analyzed by

[0129]

[0130] NMR (figure 5a)) and resulted to be composed of DL-DHAA monolactone with a yield of 55%, DL-DHAA with a yield of 19% and DL-GabDil with a yield of 17%. The remaining part of the reaction mixture was distilled with a rotavapor (70 °C) to remove the solvent under heat and dried with a mechanical pump. A white solid was recovered and, as can be observed from the

[0131]

[0132] NMR spectrum (figure 5b)), the removal of the solvent under heat favors dilactonization, leading to a greater formation of the product DL-GabDil.

[0133] Example 3: Catalytic hydrogenation of GABOH in tetrahydrofuran

[0134] O OH HOV

[0135] Pd,'G {5%}ui iS

[0136]

[0137] o OH 0

[0138] 504 mg of Pd / C (50% moisture) were weighed in a flask, to which acetic anhydride (10 mL) was added. The mixture was stirred at room temperature for one night to obtain an anhydrous catalyst. The following day, after decantation, the catalyst was washed three times with 10 mL of tetrahydrofuran and then filtered through a Buchner funnel. 502 mg of GABOH (97.8% purity) were weighed in another flask to which 15 mL of tetrahydrofuran were added together with the anhydrous catalyst and, by means of a balloon, dry hydrogen was used. After 23 hours, the reaction was stopped and the crude was filtered and the solvent was removed by rotavapor and mechanical pump. A sample of 13.56 mg was dissolved in DMSO and analyzed by 'H NMR (figure 6).From the NMR spectrum, it can be observed that, with a 100% conversion of the reagent, the products are DL-DHAA monolactone with a yield of 76%, DL-DHAA with a yield of 19% and DL-GabDil with a yield of 5%.

[0139] Example 4: Catalytic hydrogenation of GABOH in ethanol

[0140] o OH O OH 1 1zO„ .... _ „.xJ I ,Ox_...

[0141] ' Sr' 'O'' 'fO PA'C <5%i HO J H ■' O f

[0142]

[0143] & OH 6 OH 6

[0144] 513 mg of 5% Pd / C (50% moisture) were weighed in a flask, to which acetic anhydride (10 mL) was added. The mixture was stirred at room temperature for one night to make the catalyst anhydrous. The following day, after decantation, the catalyst was washed three times with 10 mL of tetrahydrofuran and then filtered through a Buchner funnel.

[0145] 1.02 g of GABOH (97.8% purity) were weighed in another flask to which 20 mL of ethanol were added together with the anhydrous catalyst and, by means of a balloon, dry hydrogen was used. After 9 hours, the reaction was stopped and the crude was filtered and the solvent was removed by rotavapor and mechanical pump. Once dried, the product obtained appears as a yellow oil; a small sample of a few milligrams was collected and analyzed by NMR in DMSO (figure 7). The signals in the 'H NMR spectrum are compatible with DL-DHAA ethyl monoester (molecular weight: 206.19 g / mol) and DL-DHAA ethyl diester (molecular weight: 234.25 g / mol). The reaction, repeated several times, showed a conversion up to 100% and a yield of the products with ester functionality up to 96%.

[0146] The hydrogenation reaction of GABOH in ethanol is diastereoselective; in fact, after hydrolysis the main product obtained was DL-DHAA, with a diastereoisomeric ratio with respect to meso-DHAA of 95 / 5.

[0147] Example 5: Hydrolysis of the reaction mixture obtained from the catalytic hydrogenation of GABOH in tetrahydrofuran

[0148]

[0149] 533 mg of solid, obtained from the reduction of GABOH in tetrahydrofuran on a 5% Pd / C catalyst according to Example 3 were weighed and transferred to a flask. 21 mLof water were then added and the flask was placed in an oil bath at 90°C for four hours. After this period, the water was removed by distillation in a rotavapor and then in a mechanical pump. This process allows the hydrolysis of all the reaction products obtained from the initial hydrogenation, with the formation of a single product: DL-DHAA. A sample was taken and analyzed by NMR in DMSO. The conversion of the process is 96%, confirmed by the3H NMR analysis (figure 8). The reaction has a diastereoselectivity for DL-DHAA of 93%, as visible in the13C NMR spectra in DMSO reported in figure 3.

[0150] Example 6: Synthesis of the (lilactone DL-GabDil by thermal dehydration from DL- DHAA OH

[0151] X ...OH AcOH

[0152] HO' '■f

[0153] OH

[0154]

[0155] In a 25 mL tinyclave (glass reactor with internal dimensions of 2.5 cm (diameter) x 10 cm), DL-DHAA (500 mg, 76.73% purity, 2.15 mmol), obtained from the hydrolysis of the reaction mixture prepared for hydrogenation in tetrahydrofuran reported in Example 5, was dissolved in 20.0 mL of acetic acid. The tinyclave was partially immersed (at the level of the internal solution) in an oil bath regulated at 140 °C under stirring for 5 hours; after this time the mixture was cooled to room temperature. The solvent of the reaction mixture was evaporated to obtain a pasty product of yellow color. The product was loaded into a sublimation apparatus and the latter was placed in an oil bath at 140 °C and 0.4 mbar. Awhite solid (173 mg, 86% purity, 1.22 mmol, 59.6% isolated yield) was recovered from the surface of the cold finger cooled by circulating tap water. The yield of the isolated product was calculated considering that the dihydroxyadipic acid used was composed of 95% of the racemic mixture DL-DHAA (which can dehydrate to dilactone).

[0156] The characterization of the DL-GabDil by TLC, 'H NMR,13C NMR, melting point, MS / MS (ESI) and ATR-FTIR provided the following results:

[0157] - TLC: Rf = 0.27, eluent hexane / AcOEt= 1 / 1 ;

[0158] - 'H NMR (CDC13), 5 (ppm): 4.95-4.94 (m, 2H), 2.38-2.28 (m, 2H), 2.18-2.09 (m, 2H), figure 9a);-13C NMR (CDC13), 5 (ppm): 166.3, 74.6, figure 9b);

[0159] - melting point: 129.2-130.8 °C;

[0160] - MS / MS (ESI): m / z 141 (60) [M - H]“, 97.2 (100) [M - H - CO2]“, figure 10a); - ATR-FTIR (cm1): 1765, 1544, 1449, 1431, 1360, 1282, 1238, 1132, 1018, 975, 911, 873, 849, 829, 799, 744, 678, 641, 607, figure 10b).

[0161] Example 7: Synthesis of DL-DHAA by hydrolysis of DL-GabDil and comparison with the products of the catalytic hydrogenation reactions of GABOH in water and tetrahydrofuran

[0162]

[0163] 26 mg of DL-GabDil were weighed in a flask and 2 mL of water are added. The flask is kept at 40°C in an oil bath for 24 hours; then, the solvent is removed by distillation with a rotavapor. The white solid obtained was analyzed by3H NMR and13C NMR in D2O; the spectra are reported in figures Ila) and 11b). The signals of the NMR analysis were found to be compatible with DL-DHAA.

[0164] Example 8: Co-polymerization (co-oligomerization) reaction of DL-GabDil with hexamethylenediamine

[0165]

[0166] 11.7 mg of DL-GabDil (85% purity, 0.07mmol) and 9.23 mg of hexamethylenediamine (0.08 mmol) were weighed in a flask and dissolved with 0.4 mL of DMSO-d6. The resulting solution was kept under stirring at room temperature for 24 hours. After this time, the mixture was transferred to an NMR tube and 'H NMR analysis was performed.

[0167] 'H NMR (DMSO, 2.5 ppm): 5 7.82-7.52 (m, 2H); 3.91-3.73(m, 2H), 3.26-2.84 (m, 4H), 2.79-2.64 (t, terminal NH2 group), 1.76-1.59 (m, 2H), 1.59-1.44 (m, 2H), 1.45-1.32 (m, 4H), 1.32-1.12 (m, 4H).A few drops of the mixture were diluted with methanol and ESI / MS analysis was performed. Table 1 reports the molar masses of the possible mass fragments; the underlined molar masses correspond to experimentally observed fragments in the ESI / MS spectrum.

[0168] From these analyses it was possible to deduce that the oligomers contain up to 11 repeating units.

[0169] (Mux n) + [(Mux n)+ MEMDA n (Mux n) + H+(Mux n) + Na+

[0170] MEMDA + H++ 2H+)] / 2

[0171] 1 259.24 281.24 375.45 188.23

[0172] 2 517.48 539.48 633.69 317.35

[0173] 3 775.72 797.72 891.93 446.47

[0174] 4 1033.96 1055.96 1150.17 575.59

[0175] 5 1292.20 1314.2 1408.41 704.71

[0176] 6 1550.44 1572.44 1666.65 833.83

[0177] 7 1808.68 1830.68 1924.89 962.95

[0178] 8 2066.92 2088.92 2183.13 1092.07

[0179] 9 2325.16 2347.16 2441.37 1221.19

[0180] 10 2583.40 2605.40 2699.61 1350.31

[0181] 11 2841.64 2863.64 2957.85 1479.43

[0182]

[0183] Table 1

[0184] n = number of repeating units

[0185] Mu= molar mass of the repeating unit

[0186] MEMDA= molar mass of hexamethylenediamine

Claims

CLAIMS1. A method for the diastereoselective synthesis of DL-2,5-dihydroxyadipic acid (DL-DHAA) of formula (I)Formula (I)comprising the catalytic hydrogenation step of 3-hydroxy-pyran-2-one-6-carboxylic acid (GABOH) of formula (II),Formula (II)wherein:- the catalytic hydrogenation step is carried out at room temperature and using H2 at atmospheric pressure in a protogenic or non-protogenic dipolar organic solvent or in water;- when the catalytic hydrogenation step is carried out in a protogenic or non-protogenic dipolar organic solvent, the method comprises a hydrolysis step in water subsequent to the catalytic hydrogenation step.

2. The synthesis method according to claim 1, wherein said non-protogenic dipolar organic solvent is a cyclic or alkyl ether, preferably is tetrahydrofuran.

3. The synthesis method according to claim 1, wherein said protogenic dipolar organic solvent is a C2-C5 alcoholic solvent, preferably ethanol or a C2-C5 monocarboxylic acid, preferably acetic acid.

4. The synthesis method according to claim 2 or 3, wherein when the solvent is a cyclic or alkyl ether, preferably tetrahydrofuran, or a C2-C5 monocarboxylic acid, preferably acetic acid, DL-DHAA monolactone of formula (III) is obtained in the catalytic hydrogenation step.'OHFormula (III)5. The synthesis method according to claim 3, wherein when the solvent is a C2-C5 alcoholic solvent, preferably ethanol, in the catalytic hydrogenation step DL-DHAA mono- and diester are obtained, preferably DL-DHAA ethyl monoester of formula (IV) and DL-DHAA ethyl diester of formula (V).OHA.OHFormula (IV)OHOH 6Formula (V)6. The synthesis method according to any one of claims 1-5, wherein when the solvent is a protogenic or non-protogenic dipolar organic solvent the diastereoselectivity is comprised between 90% and 99%, preferably is comprised between 93% and 95%.

7. The synthesis method according to claim 1, wherein when the solvent is water the diastereoselectivity is comprised between 51% and 80%, preferably is comprised between 60% and 66%.

8. The synthesis method according to any one of claims 1-7, wherein GABOH is obtained from aldaric acids from renewable sources.

9. The synthesis method according to any one of claims 1-8, wherein the catalyst is Pd / C.

10. A method for the synthesis of the dilactone DL-2,5-dioxabicyclo[2.2.2]octane-3,6-dione (DL-GabDil) of formula (VI) comprising the following steps:Formula (VI)a) synthesizing DL-DHAA according to any one of claims 1 to 9; andb) thermally dehydrating the DL-DHAA synthesized in step a), obtaining DL-GabDil.

11. The synthesis method according to claim 10, wherein step b) takes place in a protogenic dipolar organic solvent, preferably a C2-C5 monocarboxylic acid, more preferably acetic acid.

12. The synthesis method according to claim 11, wherein step b) takes place by a mode chosen from:- dehydration in an autoclave at a temperature comprised between 110°C and 140°C, preferably 140 °C at pressures comprised between 1 and 2 bar;- dehydration with partial distillation of the solvent;- dehydration with solvent at reflux with subsequent partial distillation of the solvent.

13. The synthesis method according to any one of claims 10-12, wherein the product obtained in step b) is purified by crystallization and / or sublimation.

14. The synthesis method according to claim 10, wherein step b) takes place under dry conditions and the product is recovered directly by sublimation.

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