MXPA99007530A - Chromatographic purification of chlorinated sucrose - Google Patents

Abstract

A process for separating, in the liquid phase, a reaction mixture which comprises a first chlorinated sucrose and at least one additional component selected from the group consisting of at least one other chlorinated sucrose different from said first chlorinated sucrose, salt and solvent, by injecting said reaction mixture onto a fixed bed of solid adsorbent and treating with a desorbent such that:(a) the first chlorinated sucrose passes through the adsorbent into a first recoverable product stream rich in said first chlorinated sucrose at a rate, which is different than the rate at which, (b) at least one of said additional components passes through the adsorbent into at least a second recoverable stream rich in said additional component.

Description

PURIFICATION CHROMATOGRAPHY OF SACAROSA CLORADA The invention relates to a process for purifying, by means of chromatography, chlorinated sucrose such as sucralose, which is a high intensity sweetener.

BACKGROUND OF THE INVENTION The selective modification of sucrose presents a great challenge of synthesis due to the multiplicity of OH reactive groups and the acid lability of the glycosidic bond. When the target of interest is the commercially important non-nutritive sweetener, sucralose, this is 4, V, 6 -. 6 - trichloro-4, V, 6 '- trideoxygalactosucrose (in the process of making a compound, the double configuration of position number 4 is reversed, therefore, sucralose is a galacto-sucrose), the difficulty consists in the need to chlorinate the less reactive positions 4- and V, while leaving position 6 intact which is more reactive. In spite of the numerous strategies developed to pre-block the 6-position, usually forming a sucrose-6-acylate such as sucrose-6-acetate and removing the blocking portion by means of hydrolysis after chlorination and in such a way reduce To the minimum the lateral reactions, the chlorinated crude product inevitably still contains some undesired di-tri- and tetra-chlorinated sucrose (hereinafter referred to as Di's, Tri's and Tet's respectively), as well as the high-boiling solvent used in the reaction and the chlorinated salts generated in the neutralization after the chlorination step. Taken together, this presents a problem of multifaceted purification and a fundamental concern regarding the economic results of the manufacture of sucralose. The prior art teaches various combinations of liquid-liquid extraction by distillation, crystallization and / or derivation to carry out said purification. We have already discovered that the adsorption technology exploiting the affinities in discrepancy with the associated components can be applied for solid adsorbents in particular, in different liquid-solid designs, alone or in combination with the aforementioned procedure, to offer significant performance advantages above the prior art. The simplest form of adsorption technology is the pulse mode, wherein a single concentrated mixture is introduced into an adsorbent column and subsequently separated into its various components under the passage of an appropriate desorbent. The axial or radial flow devices can be used, depending on the pressure drop needs of the system. Figure 1 represents a generic separation in this mode from a mixture of components (or bands of components), A, B, and C, where the affinity for the adsorbent follows an order. A > B > C, and to, through is indicated an increase in the elution time (or in the length of the column). Operationally, the take-off port can be placed in position 3 or later, if all 3 bands need resolution; or at any point along a continuous faith, if some degree of overlap is tolerated. Ultimately, if the focus is exclusively on purifying A and C, without any relation to B, one option is to take only the first and last portions of the overlapping profile at t2 and mix the center cut with fresh feed material; the composite that is recycled back to it, or cascaded to, a second column. In these continuous pulse modes, maximum productivity is sought by operating very close to the minimum acceptable resolution and minimizing the interval between the power pulses; in effect, keeping to a minimum the amount of desorbent used with that which just prevents the leading edge of a pulse from reaching the back edge of the pulse that immediately precedes it. The true continuous operation is also possible, demanding a simultaneous flow of feed material, of desorbent and takeoff (s). In an approach, the so-called continuous annular chromatography (CAC), in which an annular column is rotated slowly on its axis, to force the feeding material and the desorbent, inje from above, to separate into helical bands in the ring - and are properly attra to discrete ports in the background. Although of continuous operation, this design resembles the pulse design in terms of its less efficient use of the adsorbent. An alternative mechanical arrangement, called a bed with simulated movement (SMB), is preferred more - since it minimizes the use of adsorbent and desorbent and maximizes take-off concentrations. It consists of a fixed bed, comprising several sections or columns in series in a closed path, each individually capable of receiving and releasing liquid flow. During the operation, the desorbent, the feedstock and the take-off ports, which are maintained in a fixed arrangement relative to each other, rotating in front, in a fixed interval (referred to as the passage of time), in a concurrent direction with the flow of liquid - however, simulating a counter-current movement of the liquid-adsorbent contact. This design has gained wide acceptance in the manufacture of a wide range of commercial chemicals, eg, xylene, ethylbenzene, high fructose corn syrup and sugar, with commercial units operating up to a diameter of 22 feet. Still further, another mode, called concurrent SMB continuum, has also been described as a continuous cascade over the overlapped fractions through a plurality of columns, using an SMB type switch-valve arrangement. From the above aspect, it is understood that in order to apply any or all of these adsorption techniques to a particular service, one must first know a pair of adsorbent-desorbent capable of carrying out the required separation, and that the Single pulse, separated from the mechanical complexity of more continuous ranges, provides the intrinsic drawing of the relative separation factors involved. This drawing or chromatogram, records the concentrations of each element in individual fractions, colle along a volumetric line, which denotes a flow of desorbent. For convenience, where the order of elution directly reflects the increasing polarity of the components, the profile is called the "normal phase". This arises when a polar adsorbent is combined with a non-polar desorbent, eg, cyclohexane on gelatinous silica. In contrast, the term "reverse phase" describes the parity of an apolar adsorbent with a polar desorder - and an elution order of decreasing polarity. A wide diversity of application is possible - both with respect to the position and the composition of the current current being treated. In cases, where the absorption step can be placed in benign aqueous environments, organic resins are allowed. When the environment contains a crude organic solvent, one is limited to the most inert absorbers, eg, molecular sieves, gelatinous silica, zeolite and activated carbon. We have now found that both classes of adsorbent, when combined with the appropriate desorbent, can be used in applicable systems over a wide range of purification services of sucralose.

BRIEF DESCRIPTION OF THE INVENTION The invention provides a process for separating, in the liquid phase, a reaction mixture comprising a first chlorinated sucrose and at least one additional component selected from the group consisting of at least one other chlorinated sucrose different from said first chlorinated sucrose, salt and solvent, by injecting said reaction mixture into a fixed bed of solid adsorbent and treating with a desorbent so that: (a) the first chlorinated sucrose passes through the adsorbent in a first stream of recoverable product rich in said first chlorinated sucrose to a regime that is different from the regime to which, (b) at least one of said components passes through the adsorbent in at least one second recoverable stream rich in said additional component.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an illustration of a generic separation of a mixture by means of absorption. Figure 2 is a chromatogram with sodium sulphonic acid resin, 4% DVD as adsorbent and water as desorbent. Figure 3 is a chromatogram with sodium sulphonic acid resin, 2% DVB as adsorbent and water as desorbent. Figure 4 is a chromatogram with sodium sulphonic acid resin, 6% DVB as adsorbent and water as desorbent. Figure 5 is a chromatogram with gelatinous silica as adsorbent and ethyl acetate (2% water) as desorbent.

Figure 6 is a chromatogram with gelatinous silica as adsorbent and ethyl acetate (2% water) as desorbent. Figure 7 is a chromatogram with gelatinous silica as adsorbent and ethyl acetate (5% methanol) as desorbent. Figure 8 is a chromatogram with sodium sulphonic acid resin, 4% DVB as adsorbent and water as desorbent. Figure A is a table showing adsorption technology options followed by unblocking with solvent removal. Figure B is a table showing the adsorption technology options followed by unblocking, with solvent removal. Figure C is a table showing adsorption as an increase in the yield attached to the crystallization. Figure D is a table showing adsorption and derivation as an increase in performance attached to the derivation and crystallization. Figure E is a table showing the adsorption as an increase in the yield attached to the derivation and crystallization.

DETAILED DESCRIPTION OF THE INVENTION In a preferred aspect, the process of the invention is used to purify sucralose. To carry out the process of the invention for the purification of sucralose, the typical chlorinated sucrose mixture contains a chlorinated mixture of di-, tri- and tetra- chlorinated sucrose of the formula: Characterized by the different chlorinated sucrose: 4, 6'- R2, R = Cl; R ,, R4, R6 = OH; R3, Rs = H r, 6'- R4, R = Cl; R ,, R3, R6 = OH; R2, R5 = H4, V- R2, R4 = Cl; Ri, R6, R7 = OH; R3, Rs = H6.6'- R1, R7 = CI; R3, R4, R6 = OH; R 2, R 5 = H 4,1 ', 6'- R 2, R, R 7 = Cl; R ,, R6, = OH; R3, R5 = H 4, r, 6'- Rs, R4, R7 = Cl; R ,, FU = OH; R2, Rs = H 6, 1 ', 6'- R1, R4, R7 = CI; R3, Re, = OH; R2, Rs = -H 4, 6, 6'- R1, R2, R7 = Cl; R4, R6, = OH; R3, Rs = H 6.4, 1 ', 6'- Ri, R2, R4, R7 = Cl; Rβ, = OH; R3, Rs = H 4, 1 ', 4', 6'- R2, R4, Rs, R7 = Cl; R1f = OH; R3, R6 = H By means of an illustrative explanation, 4,6'-dichlorosacrose is represented by the formula when R2 and R7 = Cl; R1, R4 and Re = OH; and R3 and R5 = H. The second entry for chlorinated sucrose 4, 1 '6 is derived from an inversion of subelements in carbon number 4, resulting in 4, 1', 6 '-trichlorosacrose, the sixth compound listed, above an epimer of sucralose, ie, 4, 1 ', 6'-trichloro-galactosucrose, the fifth compound listed. The invention utilizes a reaction mixture comprising a first chlorinated sucrose and at least one additional component selected from a group consisting of at least one other chlorinated sucrose different from said first chlorinated sucrose, salt and solvent. When used to purify sucralose, the reaction mixture used in the invention can be the neutralized reaction product of the chlorination of sucrose-6-ester published in Walkup et al., U.S. Patent No. 4,980,463, which publication here It is incorporated as a reference. In that case, the reaction mixture will contain sucralose-6-ester (such as sucralose-6-acetate or sucralose-6-benzoate), probably at least one other chlorinated sucrose (including esters thereof); the tertiary amido solvent for the chlorination reaction (preferably N, N-dimethylformamide); various salt byproducts by the reaction of chlorination and neutralization (including alkaline, alkali metal oxides, ammonium and alkali metal chlorides, for example, sodium chloride and dimethylamine hydrochloride, as well as alkali metal formats such as sodium formate); and water. The sucralose-6-ester is represented by the formula shown above where R2, R4 and 7 = Cl; R1 = an acyloxic group such as acetoxic or benzozole; R6 = OH, and R3 and Rs = H. The reaction mixture in this case may contain other chlorinated sucrose which are also esterified at position 6. On the other hand, the chlorination reaction mixture (produced by the Walkup et al. .) can be subjected to steam removal or the like to remove the tertiary amido solvent (as published in Navia et al., US Pat. No. 5,530,106, the publication of which is incorporated herein by reference), followed by hydrolysis for remove the 6-acyl portion, to produce another reaction mixture that can be used in the purification process of the invention. In this case, the reaction mixture used in the process of this invention will contain sucralose; probably other chlorinated sucrose; various salt byproducts by the reaction of chlorination and neutralization (including alkaline, alkali metal oxides, ammonium and alkali ammonium chlorides, for example, sodium chloride and dimethylamino hydrochloride, as well as alkali metal formats such as sodium formate); Water; probably a small amount (less than 1 or 2%, by weight, of a reaction mixture) of a tertiary amido solvent; and possibly some leftover sucrose-6-ester compounds (in the case where the hydrolysis to remove the 6-acyl moiety was not complete). Another reaction mixture that can be used in the process of the invention can be produced from the removal by steam and a hydrolyzed product of the procedure published by Navia et al., By recrystallization (as also published in Navia et al. ) to remove salts and some of the other (that is, non-sucralose) chlorinated sucrose, most di's. In this case, the reaction mixture used in the invention will contain sucralose and other chlorinated sucrose (most tri's and tetra's); an organic solvent, such as ethyl acetate; and a small amount of water. Figure A presents a set of schemes, particular to a situation, characterized in that first the high-boiling chlorinated solvent, generally an amide such as N, N-dimethylformamide, is removed and the raw chlorinated product unblocked (as by alkaline hydrolysis to remove the acyl group of, for example, sucralose-6-acetate). The emerging aqueous stream can be purified from unwanted salts, Di's, Tri's and Tet's in any of four broad ways; three of which involve separating the purification load between the extraction and the adsorption variously - the order of which is not important. The fourth example, extending the adsorption alone, will be recognized as the main modality for demonstration purposes of this invention, involving as it does, the broadest scope of elements to be separated; the adsorption charges being in each of the other three examples only subsets thereof. Figure 2 presents the results obtained with a reverse phase system, using a sodium sulphonic resin based on polystyrene, with a crosslink of 4% divinylbenzene, as an adsorbent, and simple water as desorbent. An elution order is displayed: salt > Di's > 6,6 'sucralose > 6.1 ', 6, > 4, 6, 6 '> Tet's We have discovered the degree of cross-linking and its resulting influence on diffusion levels, important in the use of these organic resin adsorbents: 2% divinylbenzene (Figure 3) and 4% (Figure 2) providing good separations, at 6% (Figure 4) and showing little or no discrimination above. Moreover, we have found that the efficiency of the separation is invariable in terms of the selection of the cation - without any significant difference found between the alkaline or the alkali metal oxide. This is maintained in marked contrast with other carbohydrate systems that are more sensitive to considerations of selectivity or stability. Accordingly, the divalent alkali metal oxides are favored with the prior art: (a) in the case of fructose / glucose, where the degree of separation largely derives from the relative ease with which these monosaccharides can orient their groups of hydroxyl to coordinately replace the water molecules held in the cationic hydration sphere, and (b) in the case of the oligosaccharides, where the alkali metals provide radical hydrolytic destruction of the substrates. An additional point that distinguishes it from the prior art is related to the observed mode of interaction. Unlike resin interactions of (a) glucose / fructose, (b) sucrose / raffinose and oligosaccharides, which all show an elution order of an increase in molecular size, reflecting the relative ranges of penetration / diffusion through The areas of the elution profile of the chlorinated saccharose preferably suggest the increase in the hydrophobicity of the components as the determining factor - more indicative in the interactions on the Van der Waais type surface. Therefore, the largest entities in our system, that is, the Tet's rather than perform early elution online according to the size exclusion behavior of the prior art, perform late elution due to their high hydrophobic nature and vice versa, the Di's perform early and not late elution due to their more hydrophilic nature as would be expected by their smaller size. Figure B represents a further set of modalities that are constructed in those of Figure A and extend the scope of back adsorption utility in the sucralose processing process to a position prior to the removal of the chlorination solvent. Again, the branch displaying only adsorption constitutes the main modality; those involving the extraction aid and / or a second adsorption shift goes into the background. Here, as shown in Figure 5, a combination of gelatinous silica as an adsorbent and ethyl acetate as a desorbent has disclosed a new approach for separating the high boiling chlorination solvent. The weakly retained amido runs above the carbohydrates near the desorbent front; where on takeoff, it is distilled into fractions - the ethyl acetate is recited as desorbent and the amido is released from its solutes immediately. This provides an alternating intense-energy less than the steam removal taught in the prior art (Navia et al, cited above). In addition, while opening the chromatogram window in the system, (Fig. 5-7) to also include the separation of carbohydrates from another with an order of elution: Tet's > 6,6 '> DMF > 6.1 ', 6' > sucralose > 4, 6, 6 '> Di's - a wider utility arises whereby we can configure a variety of purification procedures based on adsorption. A general approach is to first purge the chromatographic ends, either by means of adsorption alone (that is, by means of successive binary separations) or by a combination of adsorption and liquid-liquid extraction. Sustaining these liquid-liquid extractions is the wide disparity in hydrophilicity seen between the three broad homologous classes, following an order: Di's > Tri's > Tet's - in line with the decreasing number of hydroxyl groups that remain in successive substitution with chlorine. In the parameter resulting from the center isometric cut, however, said differences in hydrophilicity between the shrinkage of the elements (6, 6 '-> sucralose> 6, 1', 6'-, 4, 6, 6, ' -) until the number of equilibrium stages required (for liquid-liquid extraction) becomes commercially prohibitive. In this key service, we have discovered that adsorption differentiates itself, in a marked way, from all other process technologies - in terms of performance and operational performance. The order of asymmetric elution (sucralose > 6, 1 ', 6' -> 4, 6, 6 '-) found in the reverse phase system (Figure 2) is particularly positive, in that it allows for coincidental removal of impurities 4, 6 '6' - and 6, 1-, 6 'by means of a simple binary division in an SMB array - transporting (as described above) all the efficiencies inherent to the continuous operation and to the maximum use of the adsorbent and desorbent. The normal phase approach (Figures 5-7), presenting a symmetric elution order (6, 1 ', 6' -> sucralose> 4, 6, 6'-) is also an option, although it demands the two separations Binary SMB mentioned or a simple variation capable of multiplying the takeoffs. In any case, it is recognized that the isomeric separation of the discovered sucralose is incomparable with the prior art. Crystallization, the only other direct competitor, widely presented, results in finite yields, and is self-limited by the activity of "poisoning" the unwanted isomers that grow in the mother liquor - even when second harvest strategies are included. The resulting mother liquor, which contains quantifiable amounts of sucralose, can only be reduced directly by adsorption, as above (Figure C). The derivation of the isometric cut from the center is, of course, also feasible, albeit with the extra operational complexity and the use of reactive, associated with the addition of two new chemical steps - that is, blocking and unblocking (Figure D and E ). In addition, the intermediate derivation, where a crystallization peresto is typically purified where the loss of the mother liquor is still obtained, similar to - although less than, those found with the non-derivation of sucralose. More embodiments are illustrated in Figures C - E, presenting our adsorption technology as an increase in performance together with these crystallization and / or derivation approaches. Finally, opportunities to design even more radical purification procedures are also possible, by applying the adsorption technology to esterified reaction mixtures prior to hydrolysis, such as those found, for example, in the procedures referenced above by Walkup et al., with US Pat. No. 4,980,463 and Navia et al., with United States Patent No. 5,530,106. In particular, the reverse phase chromatographic drawing, as detailed in Figure 8, showing an order of elution, sucralose >; DiCI monoacetates > sucralose-6-acetate, can be variously exploited to purify, sucralose-6-acetate, so that the next deacetylation directly yields pure sucralose.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. A process for separating, in the liquid phase, a reaction mixture comprising a first chlorinated sucrose and at least one additional component selected from the group consisting of at least one other chlorinated sucrose different from said first chlorinated sucrose, salt and solvent , by injecting said reaction mixture into a fixed bed of solid adsorbent and treating with a desorbent so that: (a) the first chlorinated sucrose passes through the adsorbent in a first stream of recoverable product rich in said first chlorinated sucrose to a regime that is different from the rate at which, (b) at least one of said additional components passes through the adsorbent in at least one second recoverable stream rich in said additional component.

2. The process according to claim 1, further characterized in that the reaction mixture includes at least two chlorinated sucrose selected from the group consisting of diclorated sucrose, trichlorinated sucrose and tetrachlorinated sucrose of the formula: Also characterized by the different chlorinated sucrose: 4, 6'- R2, R7 = Cl; R |, R4, R © = OH; R3, R5 = H1 1 '', 66 '' - R4, R = CI; R ,, R3, R6 = OH; R2, R5 = H 4, r- R2, R4 = Cl; R ?, R6, R = OH; R3, Rs = H6.6'- R1, R7 = Cl; R3, R4, e = OH; R2, R5 = H 4, 1 ', 6'- R2, R4, R7 = Cl; R |, Re, = OH; R3, R5 = H 4, 1 ', 6'- Rs, R4, R7 = Cl; R ?, R4, = OH; R2, R5 = H 6 6, 11", ,, 6 6" -R ?, R4, R7 = CI; Rs, R6, = OH; R2, R5 = H 4, 6, 6'- R1, R2, R = Cl; R4, Re, = OH; R3, R5 = H 6, 4, 1 ', 6'- Ri, R2, R4, R = Cl; Re, = OH; R3, R5 = H 4, 1 ', 4', 6'- R2, R4, R5, R7 = Cl; R1, = OH; R3, Rg = H

3. The process according to claim 1, further characterized in that the reaction mixture is a current of the current process used in the preparation of sucralose.

4. The process according to claims 1, 2 or 3 further characterized in that the salt includes a salt selected from a group consisting of alkalines, alkali metal oxides, ammonium and alkali ammonium chlorides.

5. The process according to claims 1, 2, or 3, further characterized in that the solvent is a tertiary amide.

6. The process according to claim 5 further characterized in that the tertiary amide is N, N-dimethylformamide.

7. The process according to claims 1, 2 and 3 further characterized in that the fixed bed solid adsorbent is gelatinous silica and the desorbent is an organic solvent.

8. The process according to claims 1, 2 or 3 further characterized in that the fixed bed solid adsorbent is a porous gelatinous resin with cation exchange and the desorbent is water.

9. The method according to claims 1, 2 or 3 further characterized in that the chromatographic separation is carried out in the pulse, continuous or continuous pulse modes.

10. The method according to claim 1, 2 or 3 further characterized in that the fixed bed adsorbent is contained within a column, the feed and desorbent material are injected at one end and the enriched or separated fractions follow a transverse axis, and are collected at the other end.

11. The process according to claims 1, 2 or 3 further characterized in that the fixed bed adsorbent is contained within a column, the feed material and the desorbent are injected into the circumference and the enriched or separated fractions follow a transverse radius, and they are collected through the internal channel in the center.

12. The method according to claim 1, 2 or 3 further characterized in that the fixed bed adsorbent is contained within a column, the feed material and the desorbent are injected through an internal channel in the center and the enriched or separated fractions., they follow a transversal radius, and are collected in the circumference.

13. The process according to claims 1, 2 or 3 further characterized in that the fixed bed adsorbent is contained within a vertically mounted rotating ring, the feed material and the desorbent are injected at the top and the enriched fractions or separate ones are collected in the background.

14. The process according to claims 1, 2 or 3 further characterized in that the fixed bed solid adsorbent is contained within several sections or columns in series in a closed path, each individually capable of receiving and releasing fluid, and equipped with a fixed arrangement of feed material, desorbent and take-off ports, which rotate forward at fixed intervals in a direction concurrent with the liquid flow, simulating counter-current movement of the fixed bed adsorbent.

15. - The process according to claims 1 or 3 further characterized in that the first chlorinated sucrose mentioned is represented by the formula: Where R2, R and R7 = Cl; Ri = an aciioxic group; R6 = OH; and R3 and R5 = H.

16. The process according to claim 15 further characterized in that the aciioxy group is an acetoxic group.

17. The process according to claim 15 further characterized in that the aciioxy group is a benzoyloxy group.