Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
  • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/10—Separation; Purification; Stabilisation; Use of additives

Definitions

• the present invention relates to a process for the purification of aminopropanediols of formula (I),
• X is H, straight or branched C 1 -C 5 alkyl, OH, halogen, N0 2 , OR and R is straight or branched C C 4 alkyl.
• 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.
• 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.
• 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.
• 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)
• WO 9845247 discloses a process for the purification of isoserinol which comprises the extraction of the free base from the starting solution with a (CrC 6 ) 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.
• 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.
• n is an integer of 0 to 3.
• Preferred aromatic aldehydes (II) have the following formula (IV): in which
• aromatic aldehydes having general formula (V)
• B and C are independently: H, straight or branched C 1 -C 5 alkyl, Cl, N0 2 , OH, OR, in which R is straight or branched C>C 4 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.
• 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.
• 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. Harold, 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.
• 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.
• 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.
• inorganic salts i.e. NaCl
• 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.
• 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.
• 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.
• an acid preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid or an acidic ion exchange resin.
• 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.
• Suitable solvents are selected from the group consisting of: esters of acetic acid with straight or branched C 1 -C 5 alcohols, C C 5 alcohols or monoalkyl ether glycols of alkylcellosolve (C 3 -C 7 ) 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.
• 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.
• aminopropanediol isoserinol or serinol
• triiodoaminoisophthalic acids triiodohydroxyisophthalic acids or similar compounds wherein the amino or phenol groups are alkylated, amidated, esterified or etherified.
• 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.
• 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
• 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 C 1 -C 5 alkyl, Cl, N0 2 , OH, OR in which R is a straight or branched C C 4 alkyl.
• a further object of the present invention are the compounds of general formula (III B)
• n is an integer of 0 to 3.
• Preferred compounds of general formula (III B) are those of general formula (VII)
• A, B, C are independently straight or branched C C 5 alkyl, Cl, N0 2 , OH, OR in which R is straight or branched C C 4 alkyl, and the enantiomers thereof.
• a fused silica capillary column (30 m x 0.25 mm I.D.; film thickness 0.25 ⁇ m) 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.
• 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-e ⁇ oxy- 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 NaHW0 4 (separately prepared by adding a suspension of 6.14 g of H2W04 tungstic acid (24.6 mmol) in 25 ml of H 2 0, with 24.6 ml of 1M NaOH and stirring for 15 minutes) and 363 g of demineralized H 2 0.
• the resulting solution is heated to 45°C, and 249.4 g (2.2 mol) of 30% H 2 0 2 solution are dropped therein in 90 minutes, keeping this temperature. After that, a temperature of 40° C is kept for 3 hrs.
• step A) 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 H 2 0/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 H 2 0 precooled to 0°C.
• Acidic titer (with 0.1N HC1): 99.3% s.a. Yield 40 % on allyl alcohol, 46% on H 2 0 2
• 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 H 2 0.
• 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
• 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 H 2 0 (1 L) is then percolated to neutral eluate, which is always discarded, and finally isoserinol is percolated with 2.5 M NH 3 .
• the resin is then washed with demineralized H20 (1.1 L) to neutral eluate.
• 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 H 2 0.
• 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 ⁇ S/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).
• 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.
• Example 3 A 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 H 2 0 at 0-2°C divided in 3 fractions.
• 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.
• Example 4 The Schiff base is recovered and isoserinol free base is liberated following the procedure described in Example 3.
• 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 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 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.
• serinol is percolated from the column by eluting with a
• Example 6 Preparation of the Schiff base without solvents
• 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%

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• 2000
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