WO2001058848A1

WO2001058848A1 - A process for the purification of 3-amino-1,2-propanediol and 2-amino-1,3-propanediol

Info

Publication number: WO2001058848A1
Application number: PCT/EP2001/001094
Authority: WO
Inventors: Carlo Distaso; Alessandro Lesignoli; Vittorio Valle
Original assignee: Bracco Imaging S.P.A.
Priority date: 2000-02-08
Filing date: 2001-02-02
Publication date: 2001-08-16
Also published as: IT1317817B1; ITMI20000194A1; ITMI20000194A0; AU2001246413A1

Abstract

The invention relates to a process for the purification of aminopropanediols having formula (I), in which D1 and D2 are independently H or CH2OH, through the formation of the Schiff base of formula (III), obtained by reaction with an aromatic aldehyde of formula (II), in which n =0-5 and X is H, straight or branched C1-C5 alkyl, OH, halogen, NO2, OR and R is straight or branched C1-C4 alkyl.

Description

A PROCESS FOR THE PURIFICATION OF 3-AMINO-l,2- PROPANEDIOL AND 2-AMINO- 3-PROPANEDIOL

The present invention relates to a process for the purification of aminopropanediols of formula (I),

(I) in which

Di and D₂ are independently H or CH₂OH, through formation of the Schiff base of formula (III), obtained by reaction with an aromatic aldehyde of formula (II), according to Scheme 1, Scheme 1

W (II) (I")

in which n = 0 — 5, and

X is H, straight or branched C₁-C₅ alkyl, OH, halogen, N0₂, OR and R is straight or branched C C₄ alkyl. The two aminopropanediols of formula (I), namely 3-amino-l ,2- propanediol (in which D₂ = H and Di = CH₂OH) and 2-amino-l,3- propanediol (in which D_t = H and D₂ = CH₂OH) also known as isoserinol and serinol, are widely used as building-block of non-ionic iodinated X- ray contrast agents, as well as in the synthesis of anti-inflammatories, analgesics and cosmetics. The major industrial application of said products lies in the synthesis of a number of non-ionic X-ray contrast agents, such as: Iohexol, Iomeprol, Iopentol, Iopromide, Ioversol, Ioxilan, Iodixanol, I op amidol. Physicians and the authorities which grant drag marketing authorizations, require drugs with very low levels of impurities in order to minimize any involved risks of side-effects or toxic effects for the patient. As far as iodinated contrast agents are concerned, such a requirement is due to the total amount of administered product, which is much higher than that of other medicaments. By way of example, the injected dose of contrast agent can reach and even exceed 150 g.

The high purity level of the compounds of formula (I) is therefore extremely important in order to avoid formation of any by-products and assure high purity standards to the final products. In literature, a number of methods for the purification of compounds (I) are reported, the most widely used being distillation under vacuum (see, for example, EP 470,004, US 5,053,545, US 4,221,740), and other procedures to remove water contained in the crude, always under reduced pressure (JP 3063251) or to decolorize the solution, again under reduced pressure (JP 3086851), and a method using styrene- divinylbenzene resins, such as XAD-2 (US 3,428,684)

The purity of the product, declared by suppliers, with an impurity content ranging from 1 to 3% (e.g. the product marketed by Aldrich or Merck) is considered unsatisfactory. WO 9845247 discloses a process for the purification of isoserinol which comprises the extraction of the free base from the starting solution with a (CrC₆) alcohol or an acetic acid ester (obtained with C Cs alcohols), followed by crystallization of the corresponding salt resulting from reaction with an acid selected from: oxalic acid, p-toluenesulfonic acid or a benzoic acid derivative.

Isoserinol free base is isolated from the crystallized product by treatment with a ion exchange resin and subsequent crystallization with an organic solvent.

The process described in the cited WO 9845247, provides purified isoserinol having contents in organic impurities <0.1% and in inorganic impurities <0.05%.

US 5,866,719 discloses a process for the purification of serinol which comprises first a salification with an acid and subsequently a crystallization of the resulting salt with an aqueous organic solution. According to this Patent, at the end of the purification the recovered product has a content in organic impurities below 0.1% and in inorganics below 0.05%. The main synthetic pathway to isoserinol is the reaction of

1,2-epoxypropanol (Glycidol) and 3-chloro-l,2-propanediol with ammonia (e.g. JP 3063251A2; DE 3830351A1 ; DE 3014129A1; DE 3014109A1 ; DE 3014098A1).

Isoserinol main organic by-products comprise glycerin, serinol, 3-chloropropane-l ,2-diol, bis(2,3-dihydroxypropyl)amine, tert-(2,3- dihy droxypropy 1) amine .

Serinol main organic by-products comprise glycerin, ethanolamine, 2,3-diaminopropanol, 1,3-diaminopropanol, 2-aminopropanol, N-methyl- l-amino-2,3-propanediol as well as some inorganic impurities and isoserinol.

The analytical procedure used to evaluate the quality of aminopropanediols is that reported by F. Uggeri et al., Journal of Cromatography, 449, 432-439, 1988. Other impurities such as inorganic acids (hydrochloric, sulfuric acids) and by-products such as 5-amino-2,4,6-triiodoisophthalic acid can also be present when isoserinol derives from the recovery of X-ray contrast agents. The main impurities percentages significantly vary depending on the type of industrial synthesis of serinol and isoserinol. It is therefore important to provide methods for the selective purification of these products from said impurities.

The complete removal of serinol from isoserinol or vice-versa is of course extremely difficult due to the similar chemical characteristics of the two compounds.

It has now surprisingly been found and this is the object of the present invention, a novel method for purification of the compounds of formula (I), which can be applied to both the free bases and the salts thereof, which consists in the formation of the Schiff base of compounds

(I) with an aromatic aldehyde having formula (II): in which

(II) n = 0-5 and X is H, straight or branched C C₅ alkyl, OH, halogen, N0₂, OR with R = straight or branched C C₄ alkyl. Preferably, n is an integer of 0 to 3.

Preferred aromatic aldehydes (II) have the following formula (IV):

in which

A, B and C are independently: H, straight or branched C C₅ alkyl, Cl , N0₂, OH, OR in which R = straight or branched C C₄ alkyl.

Particularly preferred are the aromatic aldehydes having general formula (V)

(V) in which

B and C are independently: H, straight or branched C₁-C₅ alkyl, Cl, N0₂, OH, OR, in which R is straight or branched C>C₄ alkyl. The process of the invention further comprises the following steps: isolation of the Schiff base of formula (III) from step a); hydrolysis of the Schiff base of formula (III) at acid pH and liberation of the aminopropanediol; recovery of the corresponding aminopropanediol. Benzaldehyde is particularly preferred.

The process of the invention is particularly advantageous in that it solves the above cited problems, making the isolation of the compounds of formula (I) extremely easy, as well as selectively removing the impurities obtained from the alkylation of the primary amino group. The formation of Schiff bases is, in fact, an extremely selective reaction, in that tertiary amines do not react and secondary amines react but they form more water-soluble products, which remain in solution.

The preparation of isoserinol Schiff base has been known in literature since 1921 (see M. Bergmann et al., Ber. 96, 936, 1921). JP 09003022 discloses the preparation of aminopropanediol Schiff bases, the esterification and the subsequent hydrolysis thereof in the presence of selected microorganisms to give 3-benzylidenamino-2- alkyloxy-1-propanol derivatives. The preparation of Schiff bases of aminopropanediols with aromatic aldehydes is also known.

W. Arlen, Canadian Journal of Chemistry, 1955, 33, 365-374, describes the preparation of the Schiff base of benzaldehyde with isoserinol, the subsequent oxidation and the cyclization of the resulting intermediate to isoquinoline derivative.

Stefaniak L., Rocz. Chem., 1967, 41(10), 1741-1748 describes the preparation of aminopropanediols Schiff bases in the presence of PhB(OH)₂ and the NMR study of their structure.

The preparation of aminopropanediols Schiff bases is cited in: D. Fenton, Tetrahedron, 1996, 52(16), 5913-5928; H. Naomi, Mol. Cryst. Liq. Cryst. Sci. Technol., 1992, 216, 265-268; Mc Casland, J. Amer. Chem. Soc, 1951, 73, 3923-3926; however the cited works do not disclose the preparation of the intermediate Schiff base for the purification of aminopropanediols. The process of the present invention comprises the preparation of the Schiff base of the mixtures of compounds having formula (I) as easy- to-recover intermediates, which are subsequently hydrolyzed to yield the purified product.

The aldehyde used for the formation of the Schiff base adduct is added to the aqueous or aqueous-alcoholic solution containing the aminopropanediol at a pH ranging from 9 to 12.

The Schiff base adduct can be prepared in aqueous solution also reversing the addition of the two reagents and in some cases it is also possible to obtain the condensation product by reacting the same reagents without solvents (see example 6) in a 1 : 1 stoichiometric ratio.

The aldehyde is preferably used in equimolar amounts or in a 5% excess to the theoretical. A further procedure that can advantageously be used during the aldehyde addition is the potentiometric control of the solution pH.

When using benzaldehyde as the aromatic aldehyde and isoserinol as the aminopropanediol, the solution pH is 11.9-12 at the beginning of the addition and it progressively decreases as the aromatic aldehyde is added to a value of 10.5-10.7, which can be considered the pH range in which the reaction is complete. Outside this pH range, the addition of aldehyde causes a further decrease in pH and excessive consumption of the aromatic aldehyde.

The poorly soluble formed Schiff base precipitates and is recovered by filtration, washing the resulting solid on the filter.

The Schiff base crystallization yield is very high also thanks to the

"salting out" effect related to the presence in the aqueous solution of inorganic salts (i.e. NaCl) from the main reaction and subsequent alkalinization with NaOH, which is necessary to reach the isolation pH value for recovering the product.

The purification and recovery of the Schiff base can be made simpler by isolating the precipitated solid product, and washing it as a humid solid, for example with a filter-press. The humid solid is then directly subjected to acid hydrolysis to obtain the purified aminopropanediol.

By this way, the drying step of the humid solid, which requires prolonged treatment in oven under vacuum at 35-45°C, may be avoided.

The Schiff base is usually isolated by filtration, centrifugation or press-filtration of the solid product, which is then suitably washed to obtain a highly pure product.

Moreover, it is also possible to avoid the drying step of the isolated product, when the humid product can be directly fed to the hydrolysis step and to the liberation in solution of the aminopropanediol.

The purified product is suspended in deionized water and subjected to acid hydrolysis, thereby liberating the aminopropanediol from the corresponding Schiff base in solution.

The Schiff base is hydrolyzed according to methods known in literature, at acid pH, for example using an aqueous or non aqueous solution of an acid, preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid or an acidic ion exchange resin.

After that, the resulting two phases are separated by filtration, if the aromatic aldehyde is solid, or by decantation if the aromatic aldehyde is liquid. The separated aromatic aldehyde is recovered, while the aminopropanediol present in the aqueous phase can be isolated with methods known in literature and described, for example, in US 5,866,719 and in WO 9845247. An advantageous method for the recovery of serinol (see e.g.

US 5,866,719, steps c and d) from the solution from the Schiff base hydrolysis, consists in the use of a system of ion exchange resins which can comprise a percolation step on a cationic resin or on a system comprising a cationic and an anionic resin, or on an anionic resin only. Alternatively, the aminopropanediol of formula (I) can be isolated, as free base, analogously to the procedure described in WO 9845247, by crystallization or extraction of the compound of formula (I) with an organic solvent. Suitable solvents are selected from the group consisting of: esters of acetic acid with straight or branched C₁-C₅ alcohols, C C₅ alcohols or monoalkyl ether glycols of alkylcellosolve (C₃-C₇) class, with variable water content. Preferred solvents are ethyl acetate, butyl acetate, 2-methoxyethanol, n-butanol, 2-butanol, ethanol and methanol. Isoserinol and serinol recovered with this procedure have a residual content of inorganic salts higher than that obtainable when recovering the product by use of ion exchange resins (see examples 1 and 3). The presence of this residual content of inorganic salts in the isolated product in amounts below 1.5%, causes no particular problems during the subsequent steps of the synthesis of the corresponding non-ionic contrast agent.

In order to purify some batches of isoserinol from the residual serinol, it has surprisingly been found that, although the solubility of the Schiff base of benzaldehyde with serinol is lower than that of the corresponding Schiff base with isoserinol, the used procedure to isolate the latter is sufficient to assure the purification of crude reaction batches having 2.5% w/w starting serinol content.

The process of the present invention can also be used for recovering isoserinol or serinol from the production of non-ionic X-ray contrast agents such as Ioexol, Iomeprol, Iopentol, Iopamidol and the like.

The crude recovered product can, in fact, contain remarkable amounts of such production by-products as aminopropanediol (isoserinol or serinol), triiodoaminoisophthalic acids, triiodohydroxyisophthalic acids or similar compounds wherein the amino or phenol groups are alkylated, amidated, esterified or etherified.

In these cases, when adsorbing resins (see e.g. US 5,811,581) can be suitably used for the purification of the end products cited above, and the compound of formula (I) can be advantageously recovered from the industrial wastes solution by the process of the invention.

The process of the invention makes it possible to recover and purify serinol (or isoserinol in case of, for example, Iomeprol) from the excess in the starting condensation reaction (2.14 mol) and to recycle it in the subsequent production batches of the non-ionic contrast agent.

The aldehyde used in the condensation reaction with aminopropanediol is recovered from both mother liquors from the filtration and washing of the Schiff base, and from the solution obtained from the hydrolysis of the Schiff base. When benzaldehyde is used in the formation of the Schiff base, this aldehyde is recovered from the aqueous solution by the conventional techniques used for the distillation of the binary water/benzaldehyde azeotrope. Benzaldehyde is recovered in an 85% yield and recycled in the subsequent cycles of preparation of the Schiff base. A further object of the present invention are the compounds of general formula (III A): in which

(HI A)

n = 0-5 and X is H, straight or branched C^Cs alkyl, OH, halogen, N0₂, OR with R = straight or branched C C₄ alkyl. Preferably, n is an integer of 0 to 3.

Preferred compounds of general formula (III) are those of general formula (VI):

in which

A, B, C are independently H, straight or branched C₁-C₅ alkyl, Cl, N0₂, OH, OR in which R is a straight or branched C C₄ alkyl.

Particularly preferred is 2-[benzylidenamino]propane-l,3-diol.

A further object of the present invention are the compounds of general formula (III B)

(III B) and the corresponding enantiomers, in which n = 0-5 and X is straight or branched -C₅ alkyl, OH, halogen, N0₂, OR with R = straight or branched C C₄ alkyl, with the proviso that Xn is always different from H. Preferably, n is an integer of 0 to 3.

Preferred compounds of general formula (III B) are those of general formula (VII)

in which

A, B, C are independently straight or branched C C₅ alkyl, Cl, N0₂, OH, OR in which R is straight or branched C C₄ alkyl, and the enantiomers thereof.

The compounds of general formulae (III A), (VI) and (III B), (VII) are prepared and isolated according to the process of the present invention.

The following examples illustrate the invention in greater detail.

Experimental Section Gaschromatographic analysis is carried out using a Hewlett-Packard HP 5890 gaschromatograph, with HP 7393A autosampler and HP 3393A integrator.

A fused silica capillary column (30 m x 0.25 mm I.D.; film thickness 0.25 μm) is used, available from J & W Scientific with liquid phase DB1701 or similar, at the following experimental conditions: injector temperature 200°C; detection temperature (FID), 220°C. Auxiliary gas flow rates: hydrogen 30 mL/min, air 350 mL/min, nitrogen 30 mL/min; transport gas flow rate: helium 1.5 mL/min. Split valve rate: 22 mL/min, splitting ratio 1/15. The following temperature timetable is used: isotherm of 130°C for 2 minutes followed by a 10°C/min gradient, which is kept for 4 min, a second isotherm of 170°C kept for 5 minutes and a second temperature gradient of 30°C/min to a temperature of 220°C which is kept for 10 minutes. Samples are automatically injected in amounts of 1 mcL.

The injected samples are derivatized according to the procedure by F. Uggeri et al., Journal of Cromatography, 449, 432-439, 1988. The following examples illustrate the invention in greater detail.

Example 1 Purification of isoserinol obtained from allyl alcohol via 2,3-eρoxy- propanol (glycidol) A) Preparation of isoserinol from allyl alcohol via 2,3-epoxy- propanol (glycidol)

A I L reactor with water jacket equipped with mechanical stirring, thermometer and reflux condenser, is loaded with 147 g (2.53 mol) of allyl alcohol, a solution of the catalyst NaHW0₄ (separately prepared by adding a suspension of 6.14 g of H2W04 tungstic acid (24.6 mmol) in 25 ml of H₂0, with 24.6 ml of 1M NaOH and stirring for 15 minutes) and 363 g of demineralized H₂0. The resulting solution is heated to 45°C, and 249.4 g (2.2 mol) of 30% H₂0₂ solution are dropped therein in 90 minutes, keeping this temperature. After that, a temperature of 40° C is kept for 3 hrs.

A 4 L reactor with water jacket equipped with thermometer, mechanical stirrer, is loaded with 2240 g of 25% ammonia (32.9 mol) and the above prepared 2,3-epoxy-l-propanol solution is dropped in 20 minutes. Due to the reaction exothermicity, temperature should be carefully monitored to prevent temperature from exceeding 35°C and ammonia from forming. The reaction is completed by stirring at a temperature of 30°C for 6 hours totally.

0.5 g of Na₂S₂0₅ and 9 g (0.061 mol) of CaCl₂ 2H₂0 are added. Ammonia and water are distilled off under vacuum in a IL reactor with water jacket (fed continuously), to a residue of 450 g. During distillation, white CaW0₄ precipitates, which is recovered at the end of the concentration by filtration.

The obtained solid is recovered and can be converted into H₂W0₄. B) Isolation of the Schiff base

The solution from step A) is cooled to room temperature, placed in a IL three-necked round-bottom flask and added with 85 g of NaCl, then 152 g (1.43 mol) of benzaldehyde are quickly added dropwise: the pH value quickly decreases from 11.8 to 10.4. The Schiff base, formed through a slightly exothermic reaction, is kept at 22°C for 15 min and subsequently cooled on H₂0/ice bath to 15°C. The solution is seeded and further cooled to 0°C, to precipitate the Schiff base as a whitish solid. The resulting suspension is kept for 1 h at this temperature, then filtered through porous septum, washing the obtained cake with 100 mL of a 20% w/w NaCl solution and subsequently with 80 x 4 mL of demineralized H₂0 precooled to 0°C.

212 g of product are obtained, which are dried under vacuum to obtain 185 g of the desired compound (1.02 mol) having the following analytical characteristics:

H₂0, % w/w: 0.1

Chlorides (NaCl), %w/w: none

Acidic titer (with 0.1N HC1): 99.3% s.a. Yield 40 % on allyl alcohol, 46% on H₂0₂

1H-NMR, ¹³C-NMR, IR and MS spectra are consistent with the structure.

C) Liberation and recovery of the free base

A 250 mL three-necked round-bottom flask equipped with mechanical stirrer, thermometer, pH metre and dropping funnel is loaded with 45 g (0.249 mol) of Schiff base of isoserinol isolated above and 90 g of demineralized H₂0. The suspension is added with about 30 g of cone. HC1 to pH 1. The solution is stirred for 15 min and the two formed phases are separated by means of separatory funnel. The upper phase, mainly containing benzaldehyde, is recycled, whereas the aqueous phase is concentrated under partial vacuum to remove the residual benzaldehyde, thus obtaining an oily residue, which is added with demineralized water to the final weight of 150 g, and percolated on 250 mL of Duolite C20MB resin (polysulfonic) in H⁺ form, discarding the eluate. Demineralized H₂0 (1 L) is then percolated to neutral eluate, which is always discarded, and finally isoserinol is percolated with 2.5 M NH₃. The resin is then washed with demineralized H20 (1.1 L) to neutral eluate.

The ammonia eluate and the washing liquor are concentrated to a residue thereby obtaining 21.9 g (0.225 mol) of product having the following analytical characteristics: G.C. purity = 99.6% s.a. G.C. by-products:

Serinol = 0.12% Area Secondary amine = none Others = 0.24% s.a. against std. H₂0% w/w = 5.95% % chlorides = 0.27% s.a.

Isolation yield = 90% Overall yield on allyl alcohol = 36 %

Example 2 Alternative recovery of the free base A 0.5 L three-necked round-bottom flask equipped with mechanical stirring, thermometer, pH metre and dropping funnel is loaded with 90 g (0.498 mol) of the Schiff base of isoserinol with benzaldehyde (obtained as in Example 1 B) and 180 g of demineralized H₂0. The suspension is added with about 60 g of cone. HC1 to pH 1. The solution is stirred for 15 min and the two formed phases are separated by means of separatory funnel. The upper phase, mainly containing benzaldehyde, is separated, whereas the aqueous phase is concentrated under partial vacuum to remove the residual benzaldehyde, thus obtaining an oily residue. The 15%) by weight aqueous solution is percolated on 0.2 L cationic AMBERJET 1200 resin regenerated in the Na⁺ form, washing then the resin to obtain an eluate with specific conductivity < 30 μS/cm.

Isoserinol is then percolated from the resin by elution with 0.2 L of 4.7% ammonia aqueous solution at a 2 BV/hr rate. The resin is washed to neutral pH with deionized water (about 1 litre). The resulting solution is concentrated to a residue to obtain 43.9 g (0.451 mol) of product having the following analytical characteristics: G.C. purity = 99.5% s.a. G.C. by-products:

Serinol = 0.1% Area Secondary amine = none Others = 0.2% s.a. against std. H₂0% w/w = 5.95% % Chlorides = 0.2% s.a.

Isolation yield 91%

Example 3 Preparation and purification of isoserinol A) Preparation of isoserinol from 3-chloropropanediol A 2 L 3-necked round-bottom flask, equipped with mechanical stirrer and thermometer, is loaded with 1362.4 g of 25% ammonia and 110.54 g (1 mol) of 3-chloropropane-l,2-diol. The solution is heated to 35°C, keeping this temperature for 90 min. The reaction is slightly exothermic and temperature should be monitored and controlled, to prevent partial evolution of ammonia. After completion of the reaction, ammonia and water are distilled off to a residue of 500 g. The concentrated solution is added at 20°C with 134.4 g of 30% sodium hydroxide, thus adjusting pH to 11.9 ÷ 12. The solution is further concentrated under vacuum, removing ammonia and water, to a residue of 500 g.

B) Preparation of isoserinol Schiff base

The solution from Example 3 A) is cooled to 20°C and 90.2 g (0.85 mol) of benzaldehyde are quickly added dropwise thereto (slightly exothermic reaction). After completion of the addition, the reaction solution has pH 10.4 ÷ 10.5. The solution is stirred for 15 min, then cooled on ice-brine bath. Once reached 15°C, the reaction is seeded and cooling is continued to 0°C. Said temperature is kept for 60 min, then the solid product is filtered. The precipitate is washed with 105 g of demineralized H₂0 at 0-2°C divided in 3 fractions.

175 g of product are obtained, which is dried to a weight of 126 g (0.703 mol) and has the following analytical characteristics:

H₂0, % w/w: none NaCl, % w/w: 0.11

Acidic titre (with 0.1N HC1): 100%

Melting point: 72°C

Yield = 70.3%

C) Isolation of the free base A round-bottom flask is loaded with 89.6 g (0.5 mol) of the above isolated isoserinol Schiff base and 180 g of demineralized H₂0. The suspension is slowly added dropwise with 47 g of 34% w/w hydrochloric acid to pH = 1. After completion of the addition, the solution is stirred for 10 min then cooled to 15-18°C, with circulating water. Stirring is discontinued and the formed two phases are separated. The upper benzaldehyde-enriched phase is separated for subsequent recycle; the lower phase is a isoserinol hydrochloride aqueous solution which is concentrated under partial vacuum (P = 2.5 kPa) to an oily residue. This is taken up with 150 g of demineralized H₂0, added with 0.25 g of sodium metabisulfite, and pH is adjusted to 11.9 by addition of 66.6 g of a 30% w/w sodium hydroxide solution. The solution is further concentrated under partial vacuum to a residue, which is the taken up with 2-butanol and brought to a 20-25°C to precipitate the inorganic salts. The salts are filtered off and the residue is washed on the filter with 2-butanol.

Washing liquors and the filtrate, which contain isoserinol, are combined and concentrated to a residue, which is taken up in demineralized water and concentrated consecutively twice, to remove the solvent.

46.7 g of isoserinol (0.488 mol) are obtained, having the following analytical characteristics: H₂0 = 3.2% w/w NaCl = 1.2% w/w Acidic titre = 95.4% s.t.q.

G.C. purity = 95.2% s.t.q. G.C. by-products: Secondary amine 0.05% Serinol 0.06% Others 0.5%

Isolation yield calculated on G.C. purity = 97.5% Overall yield from 3-chloropropane-l,2-diol = 69%

Example 4 The Schiff base is recovered and isoserinol free base is liberated following the procedure described in Example 3.

Using 50 g of Schiff base (0.279 mol) the procedure of example 3 is followed, and the aqueous solution from the acid hydrolysis is added with 100 g of dem. H₂0, then with 0.14 g of sodium metabisulfite. pH is adjusted to 11.9 by addition of 36 g of a 30% w/w sodium hydroxide solution. The resulting solution is further concentrated under partial vacuum (P = 2.5 kPa) to a residue, which is taken up with ethyl acetate and brought to 20-25°C to precipitate the inorganic salts. The salts are filtered off and the residue is washed on the filter with ethyl acetate. Washing liquors and the filtrate, which contain isoserinol, are combined and concentrated to a residue, which is taken up in demineralized water and concentrated consecutively twice, to remove the solvent.

24.7 g (0.264 mol) of isoserinol are obtained, having the following analytical characteristics: H₂0 = 1.5% w/w NaCl = 0.7% w/w Acidic titre = 97.4 % s.t.q. G.C. purity = 97.2% s.t.q. G.C. by-products:

Secondary amine 0.04% Serinol 0.05% Others 0.5%

Isolation yield calculated on G.C. purity = 94.6% Overall yield on 3-chloropropane-l,2-diol = 66.5%

Example 5

Recovery of serinol from acetylserinol solutions

The aqueous solution from Iopamidol production wastes (prepared following the synthetic procedure disclosed in US 5,811,581) weighing 1.8 kg and containing 0.16 kg (1.2 mol) of acetylserinol, is placed in a 2 L reactor with water jacket equipped with of reflux condenser, thermometer and mechanical stirrer. The aqueous solution is partially concentrated to a volume of about 0.6 L and added with 0.14 kg of a 34% HC1 solution to hydrolyze acetylserinol. The resulting solution is heated to mild reflux and kept at this temperature (T=100°C) for 1 hour. After completion of the hydrolysis of acetylserinol to serinol, the solution is further concentrated to a residue, taken up with 0.5 L of dem. water and adjusted to pH 11.9 ÷ 12 by addition of a cone. NaOH solution. The resulting solution is kept under mechanical stirring and added in 30 minutes with 133.7 g (1.26 mol) of benzaldehyde. Stirring is continued for 20 minutes, then the solution is cooled (seeding at 15°C) to 0 ÷ 5°C, keeping this temperature for 1 hour. The resulting solid is filtered through porous septum and washed three consecutive times with demineralized water precooled to 0-2°C. The recovered solid, weighing 224.5 g, is loaded in portions in a 2L reactor with water jacket equipped with mechanical stirrer, thermometer, and dropping funnel containing 0.3 L of dem. water. 34% hydrochloric acid is dropped into the suspension until pH = 1. After completion of the addition, the solution is kept under mechanical stirring for 20 minutes, then cooled to 15-18°C; stirring is discontinued and the solution is decanted to separate the two formed phases. The upper phase containing benzaldehyde is separated for further recovery of the aldehyde, the lower phase containing the serinol hydrochloride solution is distilled under vacuum to an oily residue, which is taken up with demineralized water. The resulting solution is percolated onto 0.84 L of Duolite C20MB resin suitably regenerated in the H+ form, discarding the eluate from the column. The column is then percolated with demineralized water to neutral eluate, that is discarded. Finally serinol is percolated from the column by eluting with a

2.5 M NH₃ solution, then the resin is washed with demineralized water to neutral eluate. The ammonia eluate and the washing liquid are concentrated to a residue to obtain 99.15 g of product (1.06 mol) having the following analytical characteristics: H₂0 = 1.4% w/w NaCl = 0.2% w/w Acidic titre = 97.4% s.t.q. G.C. purity = 97.2% s.t.q.

G.C. by-products: Secondary amine 0.04% Isoserinol 0.1% Others 0.5% Isolation yield calculated on G.C. purity =88.3%

Example 6 Preparation of the Schiff base without solvents Preparation of 3-[4-nitrobenzylidenamino] propane- 1 ,2-diol A 0.5 L round-bottom flask equipped with thermometer and mechanical stirrer is added with 52.4 g (0.332 mol) of 4-nitrobenzaldehyde and 30.3 g (0.332 mol) of isoserinol prepared as in Example 3 A. The resulting mass is kept under mechanical stirring for 2 hours at 23°C and subsequently added with 200 ml of demineralized water. The solution is cooled to 0-5°C and kept at this temperature for 1 hour. The precipitated solid is filtered and washed on the filter with 100 ml of demineralized water. The recovered product, weighing 84.3 g, is dried to a weight of 66.6 g, and has the following analytical characteristics:

Acidic titre = 98.9% s.t.q. Water content (KF): 0.05%

Yield: 88.5%

1H-NMR, ¹³C-NMR, IR and MS spectra are consistent with the indicated structure. Example 7

Following a procedure similar to that described in Example 6, the Schiff bases corresponding to the products reported in Table I are prepared and isolated.

Table I, preparation of Schiff bases, example 7

1H-NMR, ¹³C-NMR, IR and MS spectra are consistent with the structures of the compounds indicated in table I. Example 8

Following a procedure similar to that described in Example IB, the compounds reported in Table II are prepared.

Table II, preparation of Schiff bases, example 8

(1) An aqueous solution of aminopropanediol is dropped into the aromatic aldehyde suspension in deionized water.

1H-NMR, ¹³C-NMR, IR and MS spectra are consistent with the structures of the compounds indicated in table II.

Claims

A process for the purification of aminopropanediols of formula (I),

(I) in which one of D} and D₂ is H and the other is CH OH, in the form of base or salts thereof, which process comprises the following steps: a) reacting a compound of formula (I) with an aromatic aldehyde of formula (II)

(II) in which n = 0 - 5, and

X is H, straight or branched C C₅ alkyl, OH, halogen, N0₂, OR with

R= straight or branched C C₄ alkyl; to form the Schiff base of formula (III)

(III) b) isolation of the Schiff base of formula (III); c) hydrolysis of the Schiff base of formula (III) at acid pH and liberation of the aminopropanediol; d) isolation of the aminopropanediol.

2. A process as claimed in claim 1, in which the aromatic aldehyde has general formula (II A)

in which m = 0 - 3 and X has the meanings as claimed in claim 1.

3. A process as claimed in claim 2, in which the aromatic aldehyde has general formula (IV)

(IV) in which

A, B, C are independently H, straight or branched C₁-C₅ alkyl, Cl, N0₂, OH, OR in which R is straight or branched C₁-C alkyl.

4. A process as claimed in claim 3, in which the aldehyde has general formula (V)

(V) in which

B and C are independently H, straight or branched C₁-C₅ alkyl, Cl, N0₂, OH, OR in which R is straight or branched - alkyl.

5. A process as claimed in claims 1 to 3, in which the aromatic aldehyde is benzaldehyde.

6. A process as claimed in claims 1 to 5, in which step a) is carried out without solvents.

7. A process as claimed in claims 1 to 6, in which hydrolysis step c) is carried out either with an acid selected from: hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid or on an acidic ion exchange resin.

8 A process as claimed in claims 1 to 7, in which in step d) aminopropanediol is recovered using a cationic ion exchange resin.

9. A process as claimed in claims 1 to 7, in which in step d) the free base is recovered by using a solvent selected from: methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, n-pentanol, ethyl acetate, butyl acetate.

10. A process as claimed in claims 1 to 9 for the recovery of compounds of formula (I) from the iodinated contrast agents production wastes.

11. Compounds of formula (III A),

in which n = 0 - 5, and

X is a H, straight or branched C C₅ alkyl, OH, halogen, N0₂, OR where R is straight or branched Cι-C₄ alkyl.

12. Compounds as claimed in claim 11, of formula (VI)

in which A, B, C have the same meanings as defined in claim 3.

13. 2-[Benzylidenamino]propane-l,3-diol.

14. Compounds of general formula (III B)

in which n and X have the same meanings as in claim 1 , with the proviso that Xn is always different from H, and the enantiomers thereof.

15. Compounds of general formula (VII), as claimed in claim 14,

in which

A, B, C have the same meanings as defined in claim 3.