DESCRIPTION

Field of application

The present invention refers to a process that can be connected both to the scope of organic synthesis in homogeneous catalysis, and to the scope of heterogeneous catalysis.

Specifically, the present invention refers to a process for synthesizing phenolic derivatives with high industrial interest in the pharmaceutical industry by using glycerol carbonate. Background art

The use of phenol derivatives in the pharmaceutical industry for synthesizing the active substance it is well known in the prior art.

Among the phenol derivatives used as scaffolds for synthesizing active substances there are compounds comprising at least one benzene ring condensed with a heterocycle.

Among the latter, phenol derivatives comprising a benzodioxane unit and bicyclic compounds comprising a phenyl fused with a carbamate are particularly attractive in the sector: 2-hydroxymethyl- l ,4-benzodioxane (HMB) and its derivatives, as well as 2(3H)-benzoxazolone and derivatives thereof, are among the most commonly represented of this class of compounds.

Specifically, 2-hydroxymethyl- l ,4-benzodioxane (HMB), 2(3H)- benzoxazolone and derivatives thereof have common structural features and are particularly useful for the use mentioned above, including: - the particular structure containing both a lipophilic part (benzene ring) and heteroatoms (O and/ or N), the latter being capable of giving hydrogen bonds, allows this class of compounds to be biologically active, including a wide range of applications; the structure allows a high versatility in the field of organic synthesis and allows the functionalization by introducing a wide variety of modifications in the development of side chains both on the aromatic ring and in the aliphatic part, maintaining a rigid base structure; - at the same time, the structural form resembles that of some molecules already provided with pharmaceutical activity, such as phenylurethane (hypnotic, analgesic and antipyretic) and coumarin (bactericide).

As for the 2-hydroxymethyl- l ,4-benzodioxane (HMB) its application is known for synthesizing active substances for use as antidepressants, antihypertensives, anxiolytics, antithrombotics, anti-inflammatories and others.

In particular, among the various synthesis paths leading to HMB, two main categories are identified, wherein a certain number of steps of reaction is envisaged for both. A first synthesis path involves using epoxy derivatives, such as glycidol, which are used as alkylating agents against catechol.

A possible synthesis path of this type is described in the publication " Short enantioselective synthesis of (R)-and (S)-2-hydroxy methyl- 1,4-benzodiox n" (A. Delgado et al., Tetrahedron letters, 1988, Vol. 29, n. 30, 3671-3674). In the synthesis proposed therein, due to the high reactivity, however, the hydroxyl group of glycidol must be previously tosylated, to avoid unwanted secondary reactions (such as the propagation of oligomerization reactions to give oligomers and heavy by-products).

In this way, the glycidol thus tosylated is used as the alkylating agent of the catechol: such reaction is carried out in dimethylformamide at 60°C for several hours (27h) in the presence of a stoichiometric amount of a base (potassium carbonate or sodium hydride).

A second synthesis path of HMB is described in the publication "A facile approach to chiral 1,4-benzodioxane toward the syntheses of doxazosin, prosympal, piperoxan, and dibozan" (A. Rouf et al., Tetrahedron Letters, 2013, 54, 6420-6422) wherein it is intended to start from an enantiomerically pure reagent of natural origin, in this case D-mannitol, to obtain the final product in the desired chiral form. The synthesis path turns out to meet little the principles of the green chemistry, due to the high number of steps during which functionalization reactions, extraction operations and other manipulations are used.

The disadvantages connected to the traditional production processes described above are various and connected to the multiple steps necessary to obtain the final product, which are aimed at maximizing the yield in a single chiral form, even by decreasing the overall productivity of the process. Furthermore, the synthesis methods mentioned above include the use of toxic, explosive and/or carcinogenic reagents, such as glycidol derivatives, epichlorohydrin or dihalogenated compounds, in order to selectively facilitate nucleophilic substitution reactions and, at the same time, to improve the syntheses in an enantioselective way. Then, not least, according to both synthesis strategies previously described, many solvents are widely used, such as DMF, DCM and DMSO, also characterized by high toxicity.

Finally, in the previously described procedures, stoichiometric quantities of an inorganic base are used, co-producing large amounts of inorganic waste to be separated and disposed of.

As for 2(3H)-benzoxazolone, its application as a scaffold is known for synthesizing active substances such as drugs for human/ animal use and as phytopharmaceuticals, compounds generally provided with a wide range of biological properties. They include: antibacterial, antifungals, analgesics, anti-inflammatory, anticonvulsants, dopaminergic, anti-tumour, HIV- 1 reverse transcriptase inhibitors, as well as supplements for controlling cholesterol.

Generally, 2(3H)-benzoxazolone and the derivatives thereof are synthesized starting from aminophenol which can undergo carbonylation with phosgene, alternatively oxidative carbonylation with carbon monoxide or reactions with urea.

The use of simple organic carbonates such as dimethyl carbonate and diethyl carbonate, as carbonylation agents for synthesizing benzoxazolones, is also known. Still, even though these processes are safer from the point of view of the plant management thanks to the lower toxicity of the reagents used, such synthesis processes reveal evident control issues in avoiding the subsequent alkylation (methylation or etHylation) of the amine group. See the publication by Y. Fu, T. Baba, Y. Ono. J. Catal. 197, 2001 , 1-97, the publication by A. H. Tamboli, H. A. Bandal, H. Kim. Chemical Engineering Journal 306, 2016, 826-831 and the publication by S. Pullaa et al. Journal of Molecular Catalysis A: Chemical 338, 201 1 , 33-43. There is a growing need to develop an effective process for synthesizing phenol derivatives with high interest in the pharmaceutical industry, including 2-hydroxymethyl- l ,4-benzodioxane (HMB), 2(3H)-benzoxazolone and the derivatives thereof which includes a limited number of synthesis steps. Furthermore, a synthesis path for obtaining the compounds mentioned above is also desirable, which does not involve the use of dangerous substances from the point of view of the safety of the plant where the process takes place and in terms of health of the operators, and which guarantees a limited consumption of solvents and raw materials. The technical problem underlying the present invention is therefore to provide a method for synthesizing 2-hydroxymethyl- l,4-benzodioxane (HMB), 2(3H)-benzoxazolone and derivatives thereof which allows to overcome the problems mentioned above and also guarantees good selectivity and high yields with respect to such product. Summary of the invention

Such technical problem is solved according to the present invention by a process for synthesizing a compound having the following general formula

(I),

wherein Y is NH or R is CH2, n is zero or 1, Z is oxygen or -CH2-OH, wherein when Y is NH, n is zero, Z is oxygen,— is a double bond, and when Y is oxygen, n is 1 , Z is -CH2-OH,— is a single bond, and A represents H or from one to four substituents independently selected among nitro, halogen, a Ci-C ₄ alkyl and a Ci-C2 alkoxyl, comprising a step in which glycerol carbonate reacts with a phenol derivative having the following general formula (II),

in which A represents H or from one to four substituents independently selected among nitro, halogen, a C ₁ -C ₄ alkyl and a C1-C2 alkoxyl, wherein Q is -NH ₂ or -OH, wherein such step is carried out in the presence of at least one catalyst with basic properties according to the acid-base theory by Bronsted-Lowry.

Advantageously, the process according to the present invention can provide that no solvent is used since the solvating capacity of glycerol carbonate is exploited.

Likewise advantageously, it is possible to select the potential substituent or the potential substituents on the aromatic ring of the compound mentioned above having general formula (II) as a function of the product having general formula (I), belonging to the 2-hydroxymethyl-l,4-benzodioxane family or 2(3H)-benzoxazolone, which is desired.

Preferably, the process according to the present invention comprises a step wherein glycerol carbonate reacts with a compound having general formula (II), wherein Q is -OH, for which the above-mentioned derivative of phenol has the following general formula (Ila) corresponding to the formula of catechol and to substituted derivatives thereof, wherein A represents H or from one to four substituents independently selected among nitro, halogen, a C1-C4 alkyl and a C1.-C4 alkoxyl, more preferably wherein A represents H.

According to such latter particular embodiment, the process according to the present invention comprises a preliminary step of synthesizing glycerol carbonate and a compound having general formula (Ha), wherein glycerol reacts with a compound having the following general formula (III),

wherein A represents H or from one to four substituents independently selected among halogen, nitro, a C1-C4 alkyl and a C1-C2 alkoxyl, wherein such preliminary step is carried out in the presence of at least one catalyst with basic properties according to the acid-base theory by Bronsted-Lowry . In other words, according to the latter embodiment glycerol carbonate and the above-mentioned compound having general formula (Ila), namely the catechol or a derivative thereof, which is substituted on the aromatic ring, can be synthesized in situ starting from glycerol and from the above- mentioned compound having general formula (III), namely pyrocatecolcarbonate (PCC, benzo- l ,3-dioxolan-2-one) or a derivative thereof, which is substituted on the aromatic ring.

Therefore, the synthesis reaction of glycerol carbonate and catechol (or of a derivative thereof) and the subsequent synthesis reaction of 2- hydroxymethyl- l,4-benzodioxane or of derivatives thereof can be carried out by means of a one-pot synthesis process, namely by conducting two reactions one after the other without resorting to separation and purification processes of the intermediate products obtained, then in this case glycerol carbonate and catechol (or derivatives thereof).

More precisely, it is possible to carry out at first the synthesis reaction of glycerol carbonate and of catechol (or one of derivatives thereof), then the subsequent synthesis reaction of 2-hydroxymethyl- l ,4-benzodioxane or derivatives thereof, simply by modifying the reaction conditions, specifically by raising the reaction temperature.

It is also preferable, according to the latter embodiment, that such preliminary step of synthesizing glycerol carbonate and the above- mentioned compound having general formula (Ila) can be carried out at a temperature between 40°C and 70°C, more preferably it can be carried out at 60°C.

Likewise preferably, the further preliminary step of synthesizing glycerol carbonate and of the above mentioned compound having general formula (Ila) can be continued for a time between 15 minutes and 1 hour, more preferably for a time equal to 30 minutes.

Furthermore, again according to the latter embodiment, the preliminary step of synthesizing glycerol carbonate and of such compound having general formula (Ila) can be carried out in the presence of the same catalyst used in the step in which glycerol carbonate reacts with such phenol derivative having general formula (Ila).

Indeed, in terms of a one-pot reaction, the removal and/ or replacement of the catalyst already present in the reaction medium previously used for synthesizing glycerol carbonate and a compound having the general formula (Ila) may not be considered. Therefore, during the subsequent step of synthesizing 2-hydroxymethyl- l ,4-benzodioxane or of derivatives thereof, it may be suitable to use the same catalyst used for the previous preliminary step and already present in the reaction medium. According to a different embodiment, the process according to the invention is carried out by carrying out the step in which glycerol carbonate reacts with the phenolic derivative having general formula (II) with a ratio between glycerol carbonate and the compound having general formula (II) between 1 and 2,5.

Preferably, the process according to the invention is carried out by carrying out the step, wherein glycerol carbonate reacts with said phenol derivative having general formula (II) , with a ratio between glycerol carbonate and the phenol derivative having general formula (II) between 1.5 and 2.

According to reasons that will be subsequently explained in the detailed description, it has been surprisingly found that with an increased amount of glycerol carbonate (greater than an equivalent with respect to the compound having general formula (II)), the reaction between the glycerol carbonate and the compound having general formula (II) allows obtaining higher conversion percentages of the latter and, consequently, higher yields of a compound having general formula (I) .

According to the present invention, the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II) can be continued in the presence of a homogeneous catalyst; preferably such homogeneous catalyst is an alkoxide of an alkaline or alkaline-earth metal.

More preferably, such homogeneous catalyst is a sodium aliphatic alkoxide and/ or a potassium aliphatic alkoxide. More preferably, such homogeneous catalyst is a primary aliphatic alkoxide, more preferably selected among one of the elements of the group consisting of sodium meth oxide, potassium methoxide, sodium eth oxide, potassium ethoxide and any combination thereof.

More preferably, such homogeneous catalyst may be sodium methoxide and, especially when the process according to the present invention is carried out in the presence of an alkaline or alkaline-earth metal alkoxide as basic catalyst, the homogeneous catalyst can be present in the medium of reaction with a molar ratio with respect to the compound having general formula (II) (the limiting reagent) between 1 / 10 and 1 / 30, preferably with a molar ratio with respect to the compound having general formula (II) equal to about 1 / 15.

When the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II) is carried out in the presence of an alkaline or alkaline-earth metal alkoxide as basic catalyst, the reaction temperature is ^" between 1 10°C and 180°C.

Preferably, when in the general formula (II) Q is -OH, the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II) can be carried out at a temperature equal to about 170°C.

Likewise preferably, when in the general formula (II) Q is-NH ₂ , the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II) can be carried out at a temperature equal to about 140°C. Preferably, in the process according to the invention, according to the embodiments described in the last three paragraphs, said step wherein glycerol carbonate reacts with said phenol derivative having general formula (II) can be continued for a time ranging from 30 minutes to 6 hours, more preferably for 1 hour. According to the present invention, in the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II), such catalyst can be a heterogeneous catalyst, preferably such catalyst can be selected among the elements of the group consisting of basic zeolite, a hydrotalcite- like material, a mixed oxide obtained from thermal treatment of a hydrotalcite-like material, an alkali-metal oxide, an alkali earth-metal oxide and any combination thereof.

Preferably, when it is a hydrotalcite-like material or an oxide obtained from thermal treatment thereof, such hydrotalcite or oxide obtained from thermal treatment of hydrotalcite comprises magnesium as the bivalent metal. Also preferably, when it is a zeolite, such heterogeneous catalyst can comprise aluminosilicates with a ratio between silicon and aluminium (SAR) lower than 18, even more preferably with a ratio between silicon and aluminium (SAR) equal to about 12.

Also preferably, when such heterogeneous catalyst is a zeolite, the latter can be a sodium exchanged zeolite (for example Na-mordenite or NaY zeolite) . Preferably, when it is an alkaline-earth metal oxide, such heterogeneous catalyst can be magnesium oxide (MgO).

Preferably, such heterogeneous catalyst can be present in the reaction environment in a weight percentage ranging from 2% to 10%, preferably equal to 5%, with respect to the weight of such compound having general formula (II).

When the process according to the present invention is carried out in the presence of a heterogeneous catalyst, the step wherein glycerol carbonate reacts with the phenol derivative having general formula (II) can be carried out at a temperature between 170° C and 250° C, preferably it can be carried out at a temperature equal to about 200° C; also preferably, such step can be continued for a time ranging from 1 hour to 8 hours, more preferably for a time equal to 6 hours.

According to the present invention, in the step wherein glycerol carbonate reacts with such phenol derivative having general formula (II), the used glycerol carbonate can be optically pure.

Indeed, the glycerol carbonate molecule has a chiral center and when during the step mentioned in the previous paragraph optically pure glycerol carbonate is used, in the form of an enantiomer R or enantiomer S, an enantiomeric excess is maintained in the product.

According to the present invention, the expression "C1-C4 alkyl" refers to any alkyl substituent having no further functional group, wherein the alkyl chain can be linear or branched.

According to the present invention, the term "hydrotalcite-type material" refers to a mineral having the general formula [M ²⁺ ₍ i_ _x) M ³⁺ _x (OH) ₂ ] ^x+ (A _x / _n ) ⁿ - * yH ₂ O, as well as hydrotalcite, that is a mineral having formula Mg6Al ₂ CO ₃ (OH) i6-4(H ₂ 0) .

The hydrotalcite-type materials have a structure comprising a double layer with Mg(OH) ₂ containing cations M ²⁺ and M ³⁺ in octahedral coordination. A ^n~ is the counterion (typically carbonate). Stable structures of hydrotalcite- type minerals are known in the range 0.25 <x <0.44, while outside these limits the high density of Mg ²⁺ or Al ³⁺ leads to the formation of Mg(OH) ₂ or Al(OH)3 respectively. Such minerals typically have basic features, set out in basic sites of the O ² -, O ^" and OH type.

According to the present invention, the expression "mixed oxide derived from the thermal treatment of a hydrotalcite-type material" refers to a mixed oxide obtained by calcination of a hydrotalcite-type material, for example hydrotalcite, at temperatures usually higher than 400°C, for example an aluminium- and magnesium-based mixed oxide.

According to the present invention, the term "zeolite" refers to a mineral (comprising a hydrated aluminosilicate) with a high porosity structure, characterized by an amount of nanometric cavities (generally between 0.3 and 0.7 nanometers). Zeolites can be of natural or synthetic origin; in the event the material is of synthetic origin, such cavities have dimensions that can be modulated as a function of the dimension of the molecules or ions you want to "trap" therein. Further features and the advantages of the present invention will become clear from the following description of preferred embodiments thereof, given by way of non-limiting example with reference to the accompanying drawings.

Brief description of drawings Figure 1 represents a first simplified reaction scheme which exemplifies some steps for synthesizing 2-hydroxymethyl- l ,4-benzodioxane according to the process of the present invention, specifically when glycerol carbonate reacts with catechol (reaction 1); furthermore, figure 1 represents a second simplified reaction scheme which exemplifies some steps of a secondary reaction which takes place during the process according to the present invention, specifically when glycerol carbonate reacts with catechol (reaction 2).

Figure 2 represents a simplified reaction scheme which exemplifies some steps for synthesizing 2(3H)-benzoxazolone according to the process of the present invention, specifically when glycerol carbonate reacts with 2- aminophenol (reaction 3)

Figure 3 represents a simplified reaction scheme which exemplifies some steps of a side reaction which takes place during the process according to the present invention, specifically during a step wherein glycerol carbonate reacts with a phenol derivative having the general formula (Ila) .

Detailed description of a preferred embodiment Figure 1 shows a simplified reaction scheme which exemplifies some steps for synthesizing a compound having general formula (I), as previously described with reference to the summary, specifically for synthesizing 2- hydroxymethyl- 1 ,4-benzodioxane according to the process of the present invention, specifically when glycerol carbonate (GlyC) reacts with a compound having general formula (II), wherein the latter is catechol (and therefore wherein A is H and Y is oxygen).

Henceforth, referring to this reaction scheme, for the sake of simplicity and not limited to, it will be mentioned as "catechol", as exemplified in figure 1, still by implicit reference to any compound having general formula (II), already described in the summary, and wherein A represents H or from one to four substituents independently selected in the group already specified in the summary and wherein Q is OH.

With reference to figure 1 , according to the present invention glycerol carbonate reacts with catechol in the presence of a basic catalyst, which can be identified with a base according to the acid-base theory by Bransted- Lowry, to give 2-hydroxymethyl- l,4-benzodioxane, water and carbon dioxide.

Specifically, each molecule of catechol reacts with a molecule of glycerol carbonate to give a molecule of 2-hydroxymethyl- l,4-benzodioxane, a molecule of water and a molecule of carbon dioxide.

More specifically, the basic catalyst has the function of activating the catechol, by deprotonating one of the two hydroxyl groups present on the aromatic ring; the hydroxyl group is therefore negatively charged and so is the aromatic ring, on which the negative charge is delocalized, thereby making the molecule {softer nucleophile thanks to the derealization of the charge on the aromatic ring) prone to an attack on the alkylene carbon less hindered of GlyC (soft electrophilic site). Through this mechanism, the formation is obtained, of an intermediate (not shown) on which the hydroxy! unit remaining on the catechol is immediately deprotonated.

Two rapid consecutive intramolecular reactions come after, at first dehydration and subsequent decarboxylation, from which an intramolecular cyclization takes place, which leads to the formation of 2- hydroxymethyl- 1 ,4-benzodioxane (HMB) .

Still with reference to figure 1, in addition to the series of reactions just described in detail, exemplified in "Reaction 1", glycerol carbonate can react with catechol to give an intermediate that instead of causing an intramolecular cyclization with formation of a six-term ring, that is the HMB, causes the formation of a seven-term ring, thus obtaining a constitutional isomer of the HMB. This secondary reaction is exemplified by the reaction scheme identified with the expression "Reaction 2". On the other hand, the isomer with a seven-term cycle is formed only to a limited extent, specifically according to a ratio isomer: HMB usually equal to about 1 :9.

Figure 2 shows a simplified reaction scheme which exemplifies some steps for synthesizing a compound having general formula (I), as previously described with reference to the summary, specifically for synthesizing 2(3H)-benzoxazolone according to the process of the present invention, specifically when glycerol carbonate (GlyC) reacts with a compound having general formula (II), wherein the latter is 2-aminophenol (and therefore wherein A is H and Y is NH). Henceforth, referring to this reaction scheme, for the sake of simplicity and not limited to, it will be mentioned as "2-aminophenol", as exemplified in figure 1 , still by implicit reference to any compound having general formula (II), already described in the summary, and wherein A represents H or from one to four substituents independently selected in the group already specified in the summary and wherein Q is NH2.

With reference to figure 2, according to the present invention glycerol carbonate reacts with 2-aminophenol in the presence of a basic catalyst, which can be identified with a base according to the acid-base theory by Bnansted-Lowry, to give 2(3H)-benzoxazolone and glycerol.

More specifically, in this case the basic catalyst has the function of activating the hydroxyl of 2-aminophenol, so as to facilitate intramolecular cyclization with formation of 2(3H)-benzoxazolone, following the nucleophilic attack on carbonyl carbon by the amino group.

However, the reaction between 2-aminophenol and glycerol carbonate does not follow the mechanism described previously for catechol: indeed, the amine group, since it is a nucleophile with hard features, preferably attacks the carbonyl carbon of glycerol carbonate (hard electro philic site), with simultaneous formation of an intermediate (not shown) .

An intramolecular cyclization follows, which causes the formation of a five- member heterocycle and the elimination of a glycerol molecule.

In general and extremely advantageously, the process according to the present invention causes, besides the formation of the desired products, the release of non-hazardous and easy to treat co-products, such as water, glycerol and carbon dioxide, wherein the latter compound can be easily removed from the reaction environment by shifting the equilibrium towards the products and speeding up the reaction kinetics. Then, as anticipated in the summary, according to a particular embodiment of the process according to the present invention, the reagents used in the formation step of HMB, namely glycerol carbonate and catechol, can be synthesized in situ in the reaction environment through a preliminary step.

Specifically, during such preliminary step, pyrocatechol carbonate, also known as PCC or benzo- l,3-dioxolan-2-one, reacts with glycerol in the presence of a basic catalyst, specifically a base according to the acid-base theory by Bronsted-Lowry, according to a ratio PCC: glycerol equal to about 1 : 1.

In detail, an equivalent of PCC reacts with an equivalent of glycerol to give an equivalent of glycerol carbonate and an equivalent of catechol.

Therefore, in a very advantageous manner, such preliminary step of synthesizing in situ glycerol carbonate and catechol leads to the formation of an equimolar amount of products (glycerol carbonate and catechol, indeed) with respect to both reagents, without the formation of by-products which could invalidate the overall yield of the reaction. In this way, once the synthesis reaction of glycerol carbonate and catechol has been completed, without arduous separation and purification steps, it is possible to carry out the synthesis step of the HMB, previously described and in accordance with the process according to the invention.

Then, with reference to figure 3, when the glycerol carbonate reacts with catechol according to the process according to the present invention, during the formation of HMB a coincident reaction can occur between water (formed during the cyclization previously described to give the final product) and glycerol carbonate to give glycerol and carbon dioxide (reaction 4).

Consistently, the reaction between the water formed in the reaction medium and glycerol carbonate which has not yet reacted with catechol, besides leading to the formation of glycerol, actually causes the consumption of glycerol carbonate; therefore, the latter is no longer available for the coincident reaction with catechol.

As a consequence, in order to compensate for the amount of glycerol carbonate subtracted from the above-mentioned side reaction, it has been advantageously made sure that glycerol carbonate reacts with catechol in the presence of an excess of glycerol carbonate.

In this regard, as it will be shown more specifically in the examples, it has been observed that when glycerol carbonate reacts with a phenol derivative having general formula (II) according to a ratio glycerol carbonate: phenol derivative having general formula (II) greater than 1 : 1, the synthesis reaction of a compound having general formula (I) leads to improved yields in terms of the obtained product of interest.

More specifically, operating under the same reaction conditions in terms of temperature and time, in the presence of a same catalyst and in equal quantities, it has been observed that the step of the process according to the present invention wherein glycerol carbonate (GlyC) reacts with a phenol derivative having general formula (II) causes the formation of a doubled amount of product of interest (compound having general formula (I), namely 2-hydroxymethyl- l,4-benzodioxane or of derivatives thereof), when the ratio GlyC:phenol derivative having general formula (II) is equal to 2: 1 , with respect to the same step performed with a ratio GlyC: phenol derivative having general formula (II) equal to 1 : 1.

Furthermore, when the glycerol carbonate reacts with 2-aminophenol according to the process according to the present invention, during the formation of 2(3H)-benzoxazolone it has been surprisingly noted that an excess of glycerol carbonate contributes to speeding up the reaction, consequently increasing the overall reaction yield.

As for the reaction temperature, in the presence of a homogeneous catalyst of the methoxide type of alkali metal or alkaline-earth metal, such as sodium methoxide, in such an amount to determine a ratio catalyst: phenol derivative having general formula (II) equal to about 1 : 15, it has been observed that during the step of the process according to the present invention in which glycerol carbonate (GlyC) reacts with phenol derivative having general formula (II) to give the desired product, different yields of the desired product are achieved (and consistently a conversion rate of the phenol derivative having general formula (II)) according to the temperature operated.

In particular, as it will be explained in the following example 1 , it has been observed that with a ratio GlyC: catechol equal to 1 : 1 , operating at a temperature of 170°C, it is possible to obtain a yield of HMB equal to about 38%, which is completely satisfactory.

As mentioned previously, according to an embodiment of the present invention, it is possible to perform a preliminary in situ synthesis step of glycerol carbonate and catechol and subsequently a synthesis step of the HMB in the presence of the same basic catalyst and to an equal extent. In particular, it has been made sure that it is possible to carry out a preliminary synthesis step of GlyC and catechol with a homogeneous catalyst of the methoxide type of alkali metal or alkaline-earth metal, such as sodium methoxide, in such an amount to determine a ratio catalyst: PCC equal to about 1 : 15, and subsequently to carry out such HMB synthesis step only by modifying the temperature conditions, namely by increasing the temperature from about 60°C to about 170°C. As a consequence, it is possible to carry out both the above-mentioned one-pot steps only by controlling the temperature of the reaction.

From the preceding description it follows that the process for synthesizing 2-hydroxymethyl- l,4-benzodioxane, of 2(3H)-benzoxazolone and derivatives thereof according to the present invention allows to obtain numerous advantages, the first of which is the possibility to obtain the desired products by avoiding the use of toxic reagents, for example halogenated compounds, or explosive and carcinogenic reagents such as epoxides.

Furthermore, the process according to the present invention includes a simplified synthesis of the HMB with a limited number of steps. In particular, according to a particular embodiment, the process according to the present invention comprises a preliminary step wherein PCC reacts with glycerol, followed only by a further synthesis step to obtain the desired compound.

Then, more generally, thanks to glycerol carbonate acting as a solvent, as well as a reagent, according to the process according to the present invention, it is possible to avoid the use of traditional organic solvents, defining a significant advantage in terms of resource economy, environment and safety.

Finally, a further advantage is that related to the fact that the process according to the present invention can be carried out also in the presence of a heterogeneous catalyst, whose use allows a simple separation of the catalyst itself from the products at the end of the synthesis.

Further characteristics and advantages of the invention will be clearer from the following examples, given by way of non-limiting example with reference to the accompanying figures.

Example 1 : synthesis of 2-hydroxymethyl- l ,4-benzodioxane with a ratio catechol:GlyC equal to 1 : 1 in the presence of a homogeneous catalyst for 1 hour at 170°C

In a two-necked flask, 0.40 g of catechol and sodium methoxide (12.8 mg) were added, in a molar ratio sodium methoxide: catechol equal to 1 : 15.

Subsequently, glycerol carbonate (GlyC) was added in equimolar amount to catechol, equivalent to 0.43 g.

Finally, the flask was provided with two reflux coolers, rinsed, filled with an inert nitrogen atmosphere (the coolers were previously locked at the ends by means of suitable caps), then heated in an oil bath, while magnetically stirring for one hour at a temperature of 170°C. Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature.

Subsequently, the reaction products were recovered and solubilized in 10 ml of HPLC acetone; then, the mixture was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses. Finally, a chromatographic gas analysis was performed using a gas- chromatograph, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector.

The desired product (HMB) is obtained with a 38% chromatographic gas yield. On the other hand, the hydrolysis of glycerol carbonate, carried out by the water formed during the main synthesis reaction of the HMB, caused the formation of a significant amount of glycerol.

Example 2: synthesis of 2-hydroxymethyl- l ,4-benzodioxane with a ratio catechokGlyC equal to 1 : 1.5 in the presence of a homogeneous catalyst for 1 hour at 170°C

In a two-necked flask, 0.178 g of catechol and sodium methoxide (5.8 mg) were added, in a molar ratio sodium methoxide: catechol equal to 1 : 15.

Subsequently, glycerol carbonate (GlyC) was over-added, so that a molar ratio cathecol:GlyC equal to 1 : 1,5 (0,287 g) can be achieved. Finally, the flask was provided with two reflux coolers, rinsed, filled with an inert nitrogen atmosphere (the coolers were previously locked at the ends by means of suitable caps), then heated in an oil bath, while magnetically stirring, for 1 hour at a temperature of 170°C. Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature.

Subsequently, the products thus obtained were solubilized in 10 ml of HPLC acetone; then, the mixture was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses. The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector.

The desired product (HMB) is obtained with a 79% chromatographic gas yield. Example 3: synthesis of 2-hydroxymethyl- l,4-benzodioxane with a ratio catechol:GlyC equal to 1:2 in the presence of a homogeneous catalyst for 1 hour at 170°C

In a two-necked flask, 0.240 g of catechol and sodium meth oxide (7.8 mg) were added, in a molar ratio, sodium methoxide: catechol equal to 1 : 15. Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol, equivalent to 0.515 g.

Finally, the flask was provided with two reflux coolers, rinsed, filled with an inert nitrogen atmosphere (the coolers were previously locked at the ends by means of suitable caps), then heated in an oil bath, while magnetically stirring for 1 hour at a temperature of 170°C.

Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature.

Subsequently, the products thus obtained were solubilized in 10 ml of HPLC acetone; then, the mixture was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses. The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector.

The desired product (HMB) is obtained with a 88% chromatographic gas yield.

Given the excellent result obtained, the test was repeated under the same conditions in order to isolate the product.

After one hour, the mixture was rapidly cooled and recovered in 10 mL of ethyl acetate. Subsequently, the solution thus obtained was washed with slightly acid water (diluted solution of HC1, pH=4, total mL= 10 mL) so as to extract the unreacted catechol.

Therefore, the organic phase containing the product was then dried with sodium sulphate, filtered and evaporated to dryness by means of a rotary evaporator, obtaining a solid comprising HMB and the related isomer with a seven-terms ring for an 85% overall yield (of which 74% HMB).

Example 4: synthesis of 2-hydroxymethyl- l ,4-benzodioxane with a ratio catechoLGlyC equal to 1:2 in the presence of a homogeneous catalyst (KOCH3) for 1 hour at 170°C

In a two-necked flask, 0.240 g of catechol and sodium methoxide (10.2 mg) were added, in a molar ratio, sodium methoxide: catechol equal to 1 : 15.

Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol, equivalent to 0.515 g.

Finally, the flask was provided with two reflux coolers, rinsed, filled with an inert nitrogen atmosphere (the coolers were previously locked at the ends by means of suitable caps), then heated in an oil bath, while magnetically stirring for 1 hour at a temperature of 170°C.

Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature.

Subsequently, the products thus obtained were solubilized in 10 ml of HPLC acetone; then, the mixture was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses.

The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector. The desired product (HMB) is obtained with a 90% chromatographic gas yield.

Example 5: synthesis of 2-hvdroxymethyl- l ,4-benzodioxane with a ratio catechol:GlyC equal to 1 :2 in the presence of a heterogeneous catalyst (MgO)

In a two-necked flask, 0.200 g of catechol and magnesium oxide (MgO) were added in an amount equal to 5% w/w with respect to catechol (10 mg).

Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol equivalent to 0.429 g.

Finally, the flask was provided with two reflux coolers, rinsed, filled with an inert nitrogen atmosphere (the coolers were previously locked at the ends by means of suitable caps), then heated in an oil bath, while magnetically stirring, for 6 hours at a temperature of 200°C.

Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature.

Subsequently, the products thus obtained were recovered in 10 ml of HPLC acetone; then, the mixture was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses.

The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector. The desired product (HMB) is obtained with a 56% chromatographic gas yield, thus proving the possibility to obtain excellent yields even in the presence of a heterogeneous catalyst.

Example 6: synthesis of 2(3H)-benzoxazolone with a ratio 2- nitrophenol:GlyC equal to 1 :2 in the presence of a homogeneous catalyst at 140°C for one hour

In a single neck flask, 0.166 g of 2-aminophenol and sodium methoxide (NaOCH3, 5 mg) were added in a molar ratio catalyst:2-aminophenol of 1: 15.

Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol equivalent to 0.362 g.

Finally, the flask was provided with a reflux cooler and heated in an oil bath, while magnetically stirring, at a temperature of 140°C for one hour.

Thereafter, the reaction is stopped and the mixture is rapidly cooled to room temperature. Subsequently, the products thus obtained were recovered and solubilized in 10 ml of HPLC acetonitrile; the mixture thus obtained was suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses.

The analyses of the reaction mixture were carried out both by chromatograph gas injections, a device by Thermo, model Focus-GC, provided with a HP- 5 capillary column and a FID detector; and by Agilent Technologies 1260 Infinity HPLC injections provided with a DAD detector and using an Agilent POROshell 120 C- 18 column for the separation.

In this way a high conversion of 2-aminophenol (90%) and a 57% yield in the corresponding benzoxazolone were obtained.

Example 7: synthesis of 2-hydroxymethyl-l ,4-benzodioxane with a ratio catechol:GlyC equal to 1 :2 in the presence of a homogeneous catalyst (NaOCH3) at 140°C, and kinetic study with variable reaction time

In a two-necked flask, 0.261 g of catechol and basic catalyst (8.5 mg, sodium methoxide) were firstly added, in a molar ratio, sodium methoxide: catechol equal to 1 : 15.

Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol equivalent to 0.560 g.

Finally, the flask was provided with two reflux coolers, rinsed and filled with an inert nitrogen atmosphere (coolers locked at the ends by means of suitable caps) and heated in an oil bath, while magnetically stirring, at a temperature of 140°C.

The reaction was repeated several times under the same conditions, varying only the reaction time, so that suitable results for a kinetic analysis can be obtained.

Each time, at the end of the reaction, the mixture was rapidly cooled to room temperature and the reaction mixture was recovered and solubilized in 10 ml of HPLC acetone, then suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses.

The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector.

The yields in the desired product (HMB) at different times are shown in Table 1 :

Table 1

Example 8: Synthesis of 2-hydroxymethyl- l ,4-benzodioxane with a ratio catechol:GlyC equal to 1 :2 in the presence of a heterogeneous catalyst (Na- mordenite) at 200°C and kinetic study with variable reaction time

In a two-necked flask, 0.200 g of catechol were initially added and an amount of Na-mordenite zeolite (SAR- 12) equal to 5% in terms of weight with respect to catechol (10 mg). Subsequently, glycerol carbonate (GlyC) was added in double molar amount with respect to catechol equivalent to 0.429 g.

Finally, the flask was provided with two reflux coolers, rinsed and filled with an inert nitrogen atmosphere (coolers locked at the ends by means of suitable caps) and heated in an oil bath, while magnetically stirring, at a temperature of 200°C.

The reaction was repeated several times under the same conditions, varying only the reaction time, so that suitable results can be obtained for a kinetic analysis.

Each time, at the end of the reaction, the mixture was rapidly cooled to room temperature and the reaction mixture was recovered and solubilized in 10 ml of HPLC acetone, then suitably diluted 50 times and finally 10 μΐ of octane were added as internal standard for the analyses. The chromatographic gas analysis was performed by means of a device, model Focus-GC by Thermo, provided with an HP-5 capillary column and a FID detector.

The yields in the desired product (HMB) at different times are shown in Table 2:

Table 2