Patent Description:
Serinol (<NUM>-amino-<NUM>,<NUM>-propanediol) is a high-value building block which finds many applications in the pharmaceutical field, for example in the manufacturing of the nonionic X-ray contrast agent Iopamidol, and more generally in the chemical industry.

Iopamidol is a radiographic contrast agent well known and widely used in daily diagnostic practice (<NPL>; <NPL>).

The industrial synthesis of Iopamidol is shown in Scheme <NUM> and described, for example, in <CIT>.

Serinol is typically prepared by chemical synthesis through several alternative ways or, more recently, by biocatalysis exploiting the activity of specific enzymes. Most of these known processes have been reviewed (<NPL>).

The approaches reported in literature display several drawbacks such as low yields, use of costly, toxic or dangerous reagents, issues in the work-up, formation of serinol/isoserinol mixtures difficult to separate and to purify.

For example, an industrial process (see <CIT>) starts from nitromethane, which may be explosive, and formaldehyde, which is carcinogen, and the intermediate is hydrogenated in the presence of heavy metals as catalysts. The presence of traces of these metals in serinol may be a problem for their toxicity, especially if serinol is employed for pharmaceutical syntheses. In other processes, dihydroxyacetone is reacted with ammonia (see <CIT>) or hydroxylamine (see <CIT>), both having toxic concerns, and again the intermediate is hydrogenated in the presence of heavy metals. In a different process epichlorohydrin, known to be carcinogen, was used as starting material (see <CIT>). Furthermore, it is possible to prepare serinol with biotechnological approaches starting from renewable resources, but these processes are characterized by low productivity and difficult isolation of the product from the fermentation broth (<NPL>).

Therefore, it would be highly desirable to find a green, safe and efficient process working in mild conditions, with cheap and readily available reagents and applicable to a large industrial scale.

It has now been found that serinol can be efficiently synthesized by reaction of glycerol, or glycerol <NUM>,<NUM>-carbonate, and urea in the presence of specific catalysts to form serinol carbamate (SC) which is then hydrolyzed to give serinol.

Glycerol and urea are two safe and low-cost commodities; the first one is for instance a by-product of biodiesel production process (<NPL>) while the second is produced on a large scale to be employed mainly as fertilizer (<NPL>).

The reaction of glycerol with urea in the presence of a catalyst is widely known for the preparation of glycerol carbonate (see for instance <CIT>), whilst a yield of only <NUM>% has been reported carrying out the same reaction in the absence of a catalyst (<NPL>).

<NPL> discloses the reaction of glycerol with urea to give serinol carbamate (SC) and isoserinol carbamate (ISC). The reaction was performed at <NUM> under vacuum for <NUM>. Among the different metal oxides tested as catalysts, only γ-Zr phosphate showed a moderate activity; however, it provided with a poor yield of <NUM>% a mixture of serinol carbamate (SC) and isoserinol carbamate (ISC) in a ratio of <NUM>/<NUM> (with the preferential formation of the regioisomer ISC).

<NPL> and <NPL> disclose Zn-based catalysts which showed a high selectivity to glycerol carbonate in the reaction of glycerol carbonylation with urea. In particular ZnAlO displayed a glycerol conversion of <NUM>% after <NUM> hours at <NUM>. Serinol carbamate however was obtained as by-product (IV), with a selectivity of <NUM>% only.

<NPL> discloses the use of La<NUM>O<NUM> as heterogeneous catalyst for the carboxylation of glycerol to give glycerol carbonate and, as co-products, serinol and isoserinol carbamates (Figure <NUM>). The conversion yields of glycerol however are quite low and no data are provided with respect to the selectivity to serinol carbamate.

<NPL> discloses the use of an heterogeneous gold based catalyst supported on a range of oxides, such as for instance MgO, for the preparation of glycerol carbonate starting from glycerol and urea. In Table <NUM> it shows that, using MgO as catalyst support, <NUM>% of glycerol is converted, however serinol carbamate (SC) is obtained only as by-product (<NUM>) with a selectivity of <NUM>%.

Differently from the known processes, the process of the present invention is surprisingly able to provide selectively serinol carbamate (SC) as the main product over glycerol carbonate (GC) and over the regioisomer isoserinol carbamate (ISC). This is mainly achieved through the selection of the specific catalysts and reaction conditions of the invention, which have unexpectedly provided serinol carbamate with good yields and good selectivity results.

The present invention is related to the synthesis of <NUM>-hydroxymethyl-<NUM>-oxazolidinone (serinol carbamate, SC), which can then be hydrolyzed to <NUM>-amino-<NUM>,<NUM>-propanediol (serinol), by reacting glycerol and urea, as shown in Scheme <NUM>.

In general, glycerol is heated with urea and a catalyst, with or without a solvent, to give <NUM>-hydroxymethyl-<NUM>-oxazolidinone (serinol carbamate, SC) as main product, which is hydrolyzed in the next step to <NUM>-amino-<NUM>,<NUM>-propanediol (serinol).

Alternatively, glycerol <NUM>,<NUM>-carbonate (GC) can be used instead of glycerol as starting material.

Object of the present invention is a process for preparing <NUM>-hydroxymethyl-<NUM>-oxazolidinone (serinol carbamate) of formula (II):
<CHM>
said process comprising the step of:.

A further object of the present invention is the process as defined above further comprising the steps of:.

The catalyst used in step i) is preferably selected from Mg, MgO, Mg(OMe)<NUM> and Mg(OH)<NUM>. Most preferably it is Mg or MgO and even more preferably it is metallic Mg. Preferably metallic Mg is in powder form. The reaction of step i) may be carried out in solventless conditions (neat) or in the presence of an aprotic polar solvent having boiling point ≥ <NUM>, preferably selected from the group consisting of diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether (triglyme), dipropylene glycol dimethyl ether (proglyde), isosorbide dimethyl ether, methoxybenzene (anisole), ethyl phenyl ether (phenetole), n-decane, n-dodecane, decahydronaphtalene (decalin), <NUM>,<NUM>,<NUM>-trimethoxypropane and hexafluoropropene polyether.

Preferably, step i) is carried out in solventless conditions or in the presence of diethylene glycol dimethyl ether.

In one embodiment, step i) is carried out in solventless conditions with Mg(OH)<NUM> or Mg as catalyst.

In another embodiment, step i) is carried out in diethylene glycol dimethyl ether(diglyme) with Mg as catalyst.

The reaction of step i) is carried out at a temperature ranging from <NUM> to <NUM>, preferably from <NUM> to <NUM>. In particular, when no solvent is used, the reaction is preferably carried out at <NUM>.

The reaction time may range from <NUM> hour to <NUM> hours, preferably from <NUM> hours to <NUM> hours.

Urea is preferably used in excess amount. The molar ratio urea/glycerol or urea/glycerol <NUM>,<NUM>-carbonate preferably ranges from <NUM>:<NUM> to <NUM>:<NUM>, more preferably it is <NUM>:<NUM>.

The molar ratio catalyst/glycerol or catalyst/glycerol <NUM>,<NUM>-carbonate preferably ranges from <NUM>:<NUM> to <NUM>:<NUM>.

The hydrolysis of step ii) is preferably carried out in the presence of an aqueous solution comprising a base selected from metal hydroxides such as LiOH, NaOH, KOH, Ca(OH)<NUM> and Ba(OH)<NUM>, preferably NaOH or KOH.

Preferably the hydrolysis is carried out in water or in a mixture of an alcohol and water such as MeOH/water, EtOH/water or <NUM>-propanol/water.

The hydrolysis step is preferably performed at reflux.

In one embodiment, the product obtained in step i) is directly used in step ii) after water addition and filtration to eliminate the insoluble catalyst and without any further purification step.

When <NUM>-amino-<NUM>,<NUM>-propanediol is converted in form of a salt, the salt is preferably chloride or oxalate. The salt of <NUM>-amino-<NUM>,<NUM>-propanediol may be obtained for instance by treatment with hydrochloric acid or oxalic acid dihydrate.

A further object of the present invention is the use of serinol produced by the process of the invention in the synthesis of Iopamidol.

In one embodiment it is provided a process for obtaining Iopamidol of formula (III):
<CHM>
said process comprising the step of preparing the intermediate of formula (IV):
<CHM>
by reacting <NUM>-amino-<NUM>,<NUM>-propanediol obtained by the process described above with the compound of formula (V):
<CHM>.

The procedures and reaction conditions are disclosed, for example, in <CIT>.

Accordingly, an object of the invention is a process for the preparation of Iopamidol (III) comprising the following steps:.

Preferably, step i) is carried out in solventless conditions (neat) or in the presence of an aprotic polar solvent having boiling point ≥ <NUM>, preferably selected from the group consisting of diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether (triglyme), dipropylene glycol dimethyl ether (proglyde), isosorbide dimethyl ether, methoxybenzene (anisole), ethyl phenyl ether (phenetole), n-decane, n-dodecane, decahydronaphtalene (decalin), <NUM>,<NUM>,<NUM>-trimethoxypropane and hexafluoropropene polyether.

More preferably step i) is carried out using Mg as catalyst and diethylene glycol dimethyl ether (diglyme) as solvent or in solventless conditions.

Preferably, the molar ratio urea/glycerol or urea/glycerol <NUM>,<NUM>-carbonate in step i) ranges from <NUM>:<NUM> to <NUM>:<NUM>, more preferably it is <NUM>:<NUM>. In one embodiment the ratio catalyst/glycerol or catalyst/glycerol <NUM>,<NUM>-carbonate in step i) ranges from <NUM>:<NUM> to <NUM>:<NUM>.

In another embodiment step i) is carried out at a temperature ranging from <NUM> to <NUM>, preferably from <NUM> to <NUM>.

A further object of the present invention is a process for obtaining Iopamidol of formula (III) comprising the step of preparing the intermediate of formula (VI):
<CHM>
by reacting <NUM>-amino-<NUM>,<NUM>-propanediol obtained by the process described above with a compound of formula (VII):
<CHM>
wherein R is a straight or branched C<NUM>-C<NUM> alkyl group. The steps and conditions for the reaction with the above compound (VII) are described, for example, in <CIT> or <CIT>.

Accordingly, it is an object of the present invention a process the preparation of Iopamidol (III) comprising the following steps:.

The above steps from vi) to ix) are preferably carried out according to the process described in <CIT>.

Preferred borates are selected from the group consisting of t-butyl-, n-propyl and ethyl borate. Esters with different alkyl groups can also be used.

Preferably, the molar ratio urea/glycerol or urea/glycerol <NUM>,<NUM>-carbonate in step i) ranges from <NUM>:<NUM> to <NUM>:<NUM>, more preferably it is <NUM>:<NUM>.

In one embodiment the ratio catalyst/glycerol or catalyst/glycerol <NUM>,<NUM>-carbonate in step i) ranges from <NUM>:<NUM> to <NUM>:<NUM>.

According to the present invention and differently from the processes of the prior art, <NUM>-hydroxymethyl-<NUM>-oxazolidinone (II) (serinol carbamate) is obtained by a one-pot reaction and the obtained carbamate, after filtration of the catalyst, can be directly hydrolyzed to give <NUM>-amino-<NUM>,<NUM>-propanediol.

As better illustrated in the following examples, the process of the present invention allows to obtain the <NUM>-hydroxymethyl-<NUM>-oxazolidinone (II) (serinol carbamate) with a good yield while providing remarkable selectivity with respect to the regioisomer <NUM>-hydroxymethyl-<NUM>-oxazolidinone (X) (isoserinol carbamate) and to glycerol <NUM>,<NUM>-carbonate (XI)
<CHM>.

Moreover, after hydrolysis, good yields of <NUM>-amino-<NUM>,<NUM>-propanediol (I) (serinol) are obtained; thus, it is provided a safe and efficient process working in mild conditions, with cheap and readily available reagents and applicable to a large industrial scale.

The reaction products were analysed by Gas Chromatography using the following instrumental parameters:.

The data obtained by Gas Chromatography analysis are reported in area %.

An amount of serinol carbamate (SC) and isoserinol carbamate (ISC) was synthesized following the procedures reported in <NPL> and used as reference standard.

An amount of glycerol <NUM>,<NUM>-carbonate (GC) was purchased from TCI Europe and used as reference standard.

Reagents, catalysts and solvents are commercially available: for instance, glycerol, diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), Mg(OH)<NUM>, and La<NUM>O<NUM> were purchased from Aldrich, urea was purchased from Fluka, magnesium was purchased from Riedel de Haen, hexafluoropropene polyether (<NPL>) was purchased from Fluorochem.

Solid Mg(OMe)<NUM> was obtained by evaporation of the methanolic solution (<NUM>-<NUM>%) purchased from Aldrich.

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium methoxide (<NUM>, <NUM> mmol, <NUM> eq) was heated at <NUM> for <NUM> hours, without any solvent. The mixture reaction was monitored by gas chromatography. The same reaction was performed with Mg as catalyst (<NUM>, <NUM> mmol, <NUM> eq) for <NUM> hours, and the results are reported in Table <NUM>, showing a yield of serinol carbamate (SC) higher than <NUM>% (GC-FID peak area %) and a selectivity of serinol carbamate vs isoserinol carbamate of at least <NUM>:<NUM>.

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq), diglyme (<NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and a catalyst selected from Mg, MgO, Mg(OH)<NUM>, Mg(OMe)<NUM> and La<NUM>O<NUM> (<NUM> eq) was heated at reflux for <NUM> hours. The mixture was monitored by gas chromatography. The results obtained using the above different catalysts in diglyme, are reported in Table <NUM>, showing a yield of serinol carbamate (SC) higher than <NUM>% (GC-FID peak area %) and a selectivity of serinol carbamate vs isoserinol carbamate ranging up to about <NUM>:<NUM>.

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq), diglyme (<NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) was heated at reflux. The mixture was monitored by gas chromatography. The results obtained after <NUM> of reaction are reported in Table <NUM>, showing a complete conversion of glycerol, with yield of serinol carbamate (SC) higher than <NUM>% (GC-FID peak area %) and a selectivity of serinol carbamate vs isoserinol carbamate of about <NUM>:<NUM>.

Glycerol (<NUM>, <NUM> mmol, 1eq) was suspended in dipropylene glycol dimethyl ether (Proglyde™, <NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) were added and the mixture reaction was heated at reflux. The reaction was monitored by gas chromatography. The results obtained after <NUM> of reaction are reported in Table <NUM>, showing a yield of serinol carbamate (SC) of about <NUM>% (GC-FID peak area %) and a selectivity of serinol carbamate vs isoserinol carbamate of about <NUM>:<NUM>.

A mixture of glycerol <NUM>,<NUM>-carbonate (<NUM>, <NUM> mmol, <NUM> eq. ), diglyme (<NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) was heated to reflux and stirred, monitoring the conversion by gas chromatography. The results obtained after <NUM> of reaction are reported in Table <NUM>, showing a complete conversion of glycerol <NUM>,<NUM>-carbonate with a yield of serinol carbamate (SC) higher than <NUM>% (GC-FID peak area %) and a selectivity of serinol carbamate vs isoserinol carbamate of about <NUM>:<NUM>.

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq), Mg (<NUM> eq), urea (<NUM>, <NUM> mmol, <NUM> eq) and a solvent selected from diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether (triglyme), isosorbide dimethyl ether, dipropylene glycol dimethyl ether (proglyde), methoxybenzene (anisole) and ethyl phenyl ether (phenetole) (<NUM>) was heated at a temperature selected in a range from <NUM> and <NUM> (depending on the solvent) and stirred. The mixture was monitored by gas chromatography. The results obtained after <NUM> hours of reaction with the different solvents are reported in Table <NUM>. The yields of serinol carbamate (SC) were higher than <NUM>% (GC-FID peak area %), with selectivity of serinol carbamate vs isoserinol carbamate up to about <NUM>:<NUM>.

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq. ), diglyme (<NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) was heated to reflux and stirred, monitoring the conversion by gas chromatography. After <NUM> hours, the reaction mixture was cooled and water (<NUM>) was added, stirring for additional <NUM> minutes. The mixture was filtered to remove magnesium and a small amount of insoluble residue. Sodium hydroxide (<NUM>, <NUM> mmol, <NUM> eq) was added to the filtrate and the mixture was heated to <NUM> for <NUM> hour. Water and the organic solvent were evaporated in vacuum and the solid residue was suspended in methanol (<NUM>) and stirred at room temperature for <NUM> hours. The insoluble residue was filtered on a Buchner funnel and the filtrate evaporated in vacuum. The residue has been redissolved in water (<NUM>), acidified to pH <NUM> with conc. HCl and concentrated to half-volume by evaporation in vacuum. The solution was charged on a column filled with Amberlite IRA <NUM> (H+-form, <NUM> bed volume). The column was eluted with water to remove inorganic salts, then with <NUM> ammonium hydroxide to elute the product. The fractions of eluate containing the product were pooled and evaporated in vacuum. The residue was taken up in water (<NUM>), heated to <NUM> and oxalic acid dihydrate was added. The solution was left overnight at room temperature and the white crystalline precipitate was collected. The crude serinol oxalate was recrystallised by water/ethanol at -<NUM>, leading to analytically pure serinol oxalate (<NUM>).

Urea (<NUM>, <NUM> mol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mol, <NUM> eq) were added to a mixture of glycerol (<NUM>, <NUM> mol, <NUM> eq. ) and diglyme (<NUM>). The mixture was heated to reflux and stirred, monitoring the conversion by gas chromatography.

When the reaction was completed, water (<NUM>) was added stirring for additional <NUM> minutes. The mixture was filtered to remove magnesium and the insoluble residue. NaOH (<NUM>, <NUM> mol, <NUM> eq) was added to the filtrate and the mixture was heated to <NUM> for <NUM>. Water and diglyme were evaporated under reduced pressure, the solid residue was suspended in methanol and stirred at room temperature for a night. The insoluble residue was filtered on a Buchner funnel and the filtrate evaporated in vacuum. Active carbon (<NUM>% w/w) was added to the residue dissolved in water (<NUM>) and acidified to pH <NUM> with conc. The suspension was heated at <NUM> for <NUM> under magnetic stirring, then filtered on celite and washed with water. The filtrate was concentrated to half volume and charged on a column filled with an ion exchange resin, Amberlite IRA <NUM> (H+-form, <NUM> bed volume). The column was eluted with water to neutral pH and then with <NUM> aqueous ammonia. The eluted fractions containing the product were pooled and evaporated in vacuum. The product was obtained as a yellow oil (<NUM>, <NUM>,<NUM>% total yield, <NUM>/<NUM> serinol/isoserinol ratio).

Urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) were added to a mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq. ) and diglyme (<NUM>). The mixture was heated to reflux for <NUM> and stirred, monitoring the conversion by gas chromatography.

When the reaction was completed, water (<NUM>) was added stirring for additional <NUM> minutes. The mixture was filtered to remove magnesium and the insoluble residue. NaOH (<NUM>, <NUM> mmol, <NUM> eq) was added to the filtrate and the mixture was heated to <NUM> for <NUM>. Water and diglyme were evaporated under reduced pressure, the solid residue was suspended in methanol (<NUM>) and stirred at room temperature for a night. The solid residue was filtered on a Buchner funnel and the filtrate evaporated in vacuum. The residue was dissolved in water (<NUM>), acidified to pH <NUM> with conc. HCl, concentrated to half volume and charged on a column filled with an ion exchange resin, Amberlite IRA <NUM> (H+-form, <NUM> bed volume). The column was eluted with water to neutral pH and then with <NUM> aqueous ammonia. The eluted fractions containing the product were pooled and evaporated in vacuum. The product was obtained as a yellow oil (<NUM>, <NUM>% total yield, <NUM>% purity by gas chromatography).

A mixture of glycerol (<NUM>, <NUM> mmol, <NUM> eq. ), diglyme (<NUM>), urea (<NUM>, <NUM> mmol, <NUM> eq) and magnesium powder (<NUM>, <NUM> mmol, <NUM> eq) was heated to reflux and stirred, monitoring the conversion by gas chromatography. The results obtained after <NUM> are reported in Table <NUM>.

Claim 1:
A process for preparing <NUM>-hydroxymethyl-<NUM>-oxazolidinone (serinol carbamate) of formula (II):
<CHM>
said process comprising the step of:
i) reacting glycerol or glycerol <NUM>,<NUM>-carbonate with urea at a temperature higher than or equal to <NUM> in the presence of a catalyst selected from Mg, MgO, Mg(OMe)<NUM>, Mg(OH)<NUM> and La<NUM>O<NUM>.