WO2002039957A2

WO2002039957A2 - Chromatographic processes for recovery of isosorbide

Info

Publication number: WO2002039957A2
Application number: PCT/US2001/047136
Authority: WO
Inventors: Sean Mark Dalziel; Daniel Albert Green; Raymond Richard Zolandz
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 2000-11-06
Filing date: 2001-11-06
Publication date: 2002-05-23
Anticipated expiration: 2003-05-06
Also published as: AU2002235166A1; WO2002039957A3

Abstract

The present invention provides a process which will allow recovery of high yields of pure isosorbide from crude reaction mixtures. More specifically, the instant invention demonstrates that isosorbide can be chromatographically separated to yield pure material, using commercial strong-acid cation exchange resins.

Description

TITLE CHROMATOGRAPHIC PROCESSES FOR RECOVERY OF

ISOSORBIDE FIELD OF THE INVENTION The present invention relates to a process for product recovery.

More specifically, the present invention relates to processes involving the chromatographic separation and recovery of isosorbide. BACKGROUND OF THE INVENTION Isosorbide (1 ,4:3,6-dianhydro-D-sorbitol) is produced from sorbitol via an acid-catalyzed reaction (Fleche et al., Starch/Staerke 38(1 ):26-30 (1986); Goodwin et al., Carbohydr. Res. 79(1 ):133-141 (1980)). In addition, a number of byproducts are formed during the reaction, from which the isosorbide must be separated. These include, but are not limited to, monoanhydrides (notably 2,5-anhydro-D-mannitol; 2,5-anhydro- L-iditol; sorbitan (1 ,4-anhydro-D-glucitol); and 3,6-anhydro-D-glucitol), dimers of the monoanhydrides, and oligomeric compounds.

Isosorbide has been produced in low volume for use in specialty applications such as pharmaceuticals. Economic processes for this and similar applications involve batch reactions in which typically only a fraction (approximately 70%) of the produced isosorbide is recovered. The fraction of material that is recovered is limited by degradation reactions which occur at elevated reboiler temperatures. Continuous reaction schemes, such as that of WO 00/14081 , have the potential for producing large volumes of isosorbide economically. For such a continuous process it is desirable to recover the product in high yield, in order to minimize ingredient costs, which is necessary if isosorbide is to be prepared at a competitive cost that enables it to be used in new applications, including but not limited to use as a monomer for modified polyesters.

US 3,160,641 describes the vacuum distillation of isosorbide which had already been recovered in an unspecified yield from a crude reaction mixture. Recovery yields of 72-77% were obtained during redistillation. It was shown that the addition of boric acid to these distillations reduced the level of periodate-reactive impurities in the distillate. Furthermore, this patent also demonstrated that anion exchange resin could remove these periodate-reactive impurities from the isosorbide that had been distilled from the crude mixture. While the yield of material in the distillation was not given, 94.8% of the material charged to the resin column was recovered. However, no bulk separation between isosorbide and the major byproducts was done using the exchange resin.

More recently, Beck mentions vacuum rectification, crystallization and chromatography as techniques suitable for isosorbide separation (Beck, R., Agro-Food-Industry Hi-Tech 7(Jan/Feb.);3-5(1996).

The latter two techniques are noted as having the disadvantage of diluting the product with water, and hence vacuum rectification was chosen as the preferred technique to recover isosorbide. Beck gives no information on how one would perform the chromatographic separation of isosorbide.

WO 00/41985 describes a process whereby high purity anhydrosugars, including isosorbide, are produced by distillation followed by recrystallization from methanol, ethanol, or ethylene glycol or melt crystallization. This approach, while providing a useful technique for producing highly pure material, does not address the issue of recovering isosorbide in high yield from the crude reaction mixture.

It is desirable to recover isosorbide in high yield from the crude reaction mixture. All previous work has shown that distillation alone is not able to accomplish this task, since the onset of degradation reactions limits the reboiler temperature to somewhere in the range of 120-140°C. The problem to be solved, therefore, is to provide a process which will allow recovery of high yields of pure isosorbide from crude reaction mixtures.

SUMMARY OF THE INVENTION The instant invention relates to a chromotographic process for the recovery of high purity isosorbide comprising the steps of separating an isosorbide fraction from a mixture containing isosorbide (e.g. a crude reaction mixture containing isosorbide) by chromatography of the mixture with a suitable solvent or solvent mixture, in the presence of a sorbent, and then drying the isosorbide extracted. The invention further relates to a process for the recovery of high purity isosorbide comprising the steps of: separating an isosorbide fraction from a reaction mixture containing isosorbide thereof by chromatography in the presence of strong-acid cation exchange resins; and followed by solution or melt crystallization of a solution of the recovered fraction. One can recycle the "mother liquid" from the crystallization step back to the chromatography step.

The invention further relates to a process for recovering of high purity isosorbide comprising: (a) distilling isosorbide from an isosorbide feed stream then

(b) recovering the isosorbide from the distillate bottom, and optionally recycling the isosorbide to a chromatography unit for separation. An optional crystallization step may be involved.

The isosorbide produced by the above processes can be contacted with ion exchange resin and or activated carbon to remove impurities. The mixture containing isosorbide may be the crude reaction product resulting from another process. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the Purity versus the Recovery Curve for Example 1.

Figure 2 illustrates the feed versus time for Example 1. Figure 3 is a diagram of the "Improved Simulated Moving Bed" chromatography process.

DETAILED DESCRIPTION OF THE INVENTION Applicants have solved the stated problem of recovering isosorbide from a mixture containing isosorbide and impurities, for example from a crude reaction mixture, by providing chromatographic separation techniques that can simultaneously achieve high product purities and yields without the need for high temperature operation. More specifically, the instant invention demonstrates that isosorbide can be chromatographically separated to yield pure material, using commercial sorbents, including strong-acid cation exchange resins. The chromatographic process can be used alone or in combination with other separation operations, in order to optimize process economics and meet specific product purity specifications. In a preferred embodiment the size range of the sorbent is in the range of 200-500 microns.

In the disclosure, a number of terms and abbreviations are used. The following definitions are provided.

"High pressure liquid chromatography" is abbreviated as HPLC. "Gas chromatography" is abbreviated as GC. Commercial operation of chromatographic separation is best carried out using any one of several simulated moving bed systems that are commercially available, or systems similar to them. All of these chromatographic systems are operated isocratically, which is to say that a single eluent solvent is used, this solvent being identical to that in which the feed is dissolved. The disadvantage of isocratic operation is that the products withdrawn from the process are diluted, as compared to their concentration in the feed solution, typically by a factor of 3 to 5. The advantage is the simplicity of the system. One avoids both regeneration of the chromatographic medium from the eluent solvent to that in which the feed is dissolved, and there is no separation required to recover the solvents from each other. Gradients in pH or ionic strength, often used in protein elution, are not required.

An unexpected complication discovered while doing chromatographic separation of isosorbide was the fact that dissolved material in the isosorbide feed can precipitate in the sorbent bed, leading to clogging of the bed and increased pressure drop. The precipitate is higher molecular weight material that is soluble in isosorbide, but not soluble in water. Thus, these solids precipitate within the column when the isosorbide feed is diluted with the eluent liquid. The feed may be pre- treated to remove these materials prior to chromatography. One such pretreatment method is to pre-dilute the sample, filter off the precipitate, then either use the diluted material as feed or reconcentrate it prior to chromatography. Membrane filtration using nanofiltration membranes or adsorption with materials, such as activated carbon, can be used as pretreatment techniques. The membranes used for filtration can be those used for nanofiltration or reverse osmosis. If, during the reaction step, production of the precipitating compounds is sufficiently reduced, then solids will not form during the chromatographic step. It was found during the course of this work that running the reactor at lower temperatures gave crude isosorbide which did not form precipitate in the chromatography beds.

The process for the recovery of purified isosorbide can be conducted at an elevated pH so as to keep byproducts dissolved during the chromatographic process. There are several possible cases in which chromatographic separation can be applied to recovering isosorbide. In the first, the separation is done by chromatography alone, followed by drying of the isosorbide. This process is the simplest. It has the advantage of requiring only a single separation operation, although any impurities that elute with the isosorbide product remain with it.

The second process, chromatography followed by either solution or melt crystallization, is capable of enriching the isosorbide purity above that produced in chromatography. There may be a recycle of the "mother liquor" from crystallization back to the chromatography step.

In the third process, the crude material from the reactor is distilled to remove as much isosorbide as is feasible (about 50% yield). The distillation bottoms are then sent to a chromatography unit for recovery of the remaining isosorbide, which may, if desired, be recycled to the distillation unit. The advantage of this system is that the size of the chromatography unit is reduced, as is the amount of feed isosorbide which is diluted with the eluent liquid. A final (optional) crystallization step may be done to meet purity requirements.

Although the largest fraction of the color in the crude feed is removed in the chromatographic step, it was shown that activated carbon is useful for removing the last traces of color from the aqueous isosorbide produced in chromatography. There may be other low-level impurities which need to be removed from the isosorbides. Organic acids (formates and acetates) may also be present. These organic acids may be removed on anion exchange resins. The particular polishing operation will depend upon the required specifications of the product isosorbide.

Numerous solids can be used in chromatographic separations, including zeolites, activated carbons, adsorbent resins, and ion cation exchange resins. While other solids might be used for the chromatographic separation of isosorbide, we have found strong-acid cation exchange resins, as available from various vendors, to be particularly suitable for this task. For a list of the major commercially available cation exchange resins, see Ion Exchange Resins, Kunin, John Wiley and Sons, Inc., Second Edition (1958), Table 13. In addition, the patent literature is replete with descriptions of the preparation of suitable cation exchange resins. See, for exchange, U.S. Pat. Nos. 2,860,109; 2,877,191 ; 2,885,371 ; 2,891 ,014; 2,898,311 ; 3,030,317; and 3,275,575, among many others. As is well known, for chromatographic separations it is best to have ion exchange particles of uniform size, and to use particles that are as small as possible. The limit on particle size is the tolerable pressure drop through the chromatographic column: for this reason commercial resins for industrial separations are typically in the range of about 250 microns to 500 microns, versus the much smaller particles (5-10 micron) used in HPLC columns. GENERAL METHODS Three basic configurations that use the chromatographic process are considered. In the first, the separation is done by chromatography alone, followed by drying of the isosorbide. The second process utilizes chromatography to perform the bulk separation of isosorbide from the byproducts, followed by crystallization from either solution or melt to achieve product purity. In the third, the crude material is distilled to remove as much isosorbide as is feasible (about 50% yield), followed by chromatographic recovery of isosorbide from the distillation bottoms, and a final (optional) distillation and/or crystallization. Note that in any of these schemes, polishing of the product isosorbide via either adsorption or ion exchange may be used, if necessary, to meet stringent purity requirements, such as those associated with polymer-grade material.

Crude isosorbide, produced by an acid acid-catalyzed hydrolysis of sorbitol, has an approximate composition, by weight, as follows: 75% isosorbide, 10% anhydro- byproducts and 15% dimers/oligomers. The crude mixture produced using mineral acids as catalyst will also contain the acid at a level of up to several percent. Standard reaction temperature was 140°C at a pressure of approximately 200 mm Hg. Some batches of crude isosorbide were produced under milder conditions, where the^" temperature was approximately 120°C.

The meaning of abbreviations is as follows: "sec" means second(s), "min" means minute(s), "h" means hour(s), "d" means day(s), "μL" means microliter(s), "mL" means milliliter(s), "ccm" means cubic centimeters per minute, "L" means liters, "mM" means millimolar, "M" means molar and "mmol" means millimole(s).

EXAMPLE 1 Chromatographic Separation of Isosorbide Using HPLC Chromatographic separation of isosorbide from impurities in the crude mixture was demonstrated using high-pressure liquid chromatography (HPLC). A Shodex® brand chromatographic column containing strong acid resin (SH1011) in the protonated (H⁺) form was used to examine mixtures of crude isosorbide. The column was thermostatted at 50°C in the oven of an Agilent 1100 HPLC instrument, with a flow of 0.50 mL/min of 0.005 M H2SO4 as eluent liquid. As seen in Table 1 , it was found that all of the components but one eluted from the column before isosorbide. Thus, with this resin, isosorbide can be chromatographically separated from other components in the mixture. In fact, it can be separated in a single binary split from all of the other components save isomannide.

Table 1

EXAMPLE 2 Chromatographic Separation of Isosorbide Using Packed Columns Three jacketed glass columns were filled with strong-acid ion exchange resin (Diaion UBK555, Mitsubishi Chemicals) that had been converted to the protonated form. The columns were 25 mm in diameter, and the total bed length was 159.7 cm. The columns were thermostatted to 50°C, and were equipped with fritted elements at each end to ensure good distribution of liquid. A 5.8 g sample of crude isosorbide solution (29.5 wt. % crude in water) prepared under standard reaction conditions was placed on the column, then a flow of eluent water at 22 g/min was passed through the column. Fractions of the fluid exiting the column were collected, each fraction being collected for 20 sec. Samples were analyzed via HPLC and gas chromatography (GC). Results are shown in Figure 1 , Figure 2 and Table 2. It is evident that the byproduct materials were eluted from the column ahead of the isosorbide. The isosorbide fractions were collected and the water removed (via vacuum distillation or other appropriate techniques) to produce purified isosorbide. Fractions were pooled to obtain approximately 97% pure isosorbide at 95% recovery of the material found in the feed. 3,6-Glu = 3,6-Anhydroglucitol

2,5-ldi = 2,5-Anhydroiditol dimer II, III, IV = dehydration products of the anhydro compounds, dimer I = sorbitol-sorbitol dehydration products dimer II = sorbitol-sorbitan dehydration products dimer III = sorbitan-sorbitan dehydration products dimer IV = sorbitan-isosorbide dehdration products

Isoslmp = unknown impurities which elute near isosorbide during

GC/MS

Unknown MA are monoanhydride compounds identified as such by

GC/MS.

(specific structures and stereochemisty not identified)

Table 2

During the course of the run precipitation of fine dark solids occurred within the chromatography bed. The precipitate deposited near the end of the column where the crude isosorbide feed entered the bed. The precipitate was found to be insoluble in water, but soluble in pure isosorbide.

Other strong acid ion exchange resins were tested with similar results. These included Dowex 50Wx8, Dowex Monomsphere 99K/320K⁺, UBK510L, UBK530(Na⁺), and Amberlite IRC-76 (H⁺). EXAMPLE 3 Chromatographic Separation of Isosorbide Using Columns A number of chromatographic runs were made using strong-acid ion exchange resin (Diaion UBK555, Mitsubishi Chemicals) that had been converted to the protonated form. A number of runs were performed on 25 mm diameter columns under conditions comparable to those in Example 2, while others were performed on columns which were 50 mm in diameter. Two columns in series, with a total column length of about 80 inches, were used in these runs. In these runs, 20 to 30 g of crude material was loaded onto the first column, then water was used as eluent, at a flow rate of 40 cc/min, to elute the material through the two columns.

As in the previous run, precipitation of fine dark solids occurred within the chromatography bed.

Isosorbide that had been chromatographically separated from other components were combined (sample denoted as "Eluate" in Table 3) was passed through a bed of activated carbon (Calgon Carbon OL 12x50) to decolorize it ("CharTreat" sample). This material, containing approximately 1.6 weight percent isosorbide, was concentrated on a rotary evaporation system at 80°C and approcimately 29 inches mercury vacuum to yield 83 g of sample. Portions of this material ("XtalFeed") were dissolved in water and recrystallized. Analysis was done on both unwashed and washed crystals. The washed crystals were analyzed in duplicate. Carbon treatment not only decolorized the Eluate, it also removed some of the remaining impurities in the isosorbide, some of which apparently reformed during the wiped film evaporation that was done to remove water from the isosorbide. The single crystallization step enhanced product purity to in excess of 99.7%.

Table 3

EXAMPLE 4 Simulated Moving Bed Chromatography of Crude Isosorbide

A sample of crude isosorbide produced under standard conditions was separated via the chromatography process disclosed in JP-A 2-49159, referred to commercially as the ISMB (Improved Simulated Moving Bed) process. See Figure 3. UBK-555 resin in the sodium form was used as sorbent. Feed material was an aqueous solution that contained 65% crude isosorbide that had been produced under standard reaction conditions. Feed was loaded onto the bed at a rate of 0.054 bed volumes per hour, and the ratio of the elutant to the feed was 3.5. The isosorbide product had a purity of 98.1%, with 91% of the isosorbide in the feed being recovered in this product. During the course of the run precipitation of fine dark solids occurred within the chromatography beds. The solids were readily dissolved in 1% sodium hydroxide, and was insoluble in methanol, isopropanol and acetone. Nuclear magnetic resonance indicated the presence of carboxylic acid groups, as well as C- H saturated alkane groups and either ammonia or nitrate.

EXAMPLE 5 Simulated Moving Bed Chromatography of Crude Isosorbide Crude isosorbide produced under the milder reaction conditions was separated a 20-bed ISEP system from Calgon Carbon Corporation. Beds were 1 inch in diameter by approximately 3 feet long, and were filled with UBK-555 resin in the Na+ form. The system was configured so that Zone I (elution zone) consisted of 4 beds, while Zone II (enrichement zone), zone III (stripping zone) and zone IV (reload zone) had 6, 5 and 5 beds respectively. Feed material was an aqueous solution that contained 61 % crude isosorbide that had been neutralized with sodium hydroxide. Process temperature was 60°C. Flow rates were varied at times during the run, but typical rates are as follows: elutant (water) rate was 19.5 ccm, the isosorbide product (extract) rate was 7.6 ccm, the feed rate was 6.0 ccm, the byproduct (raffinate) rate was at 7.4 ccm. The "recycle" stream, at 11.5 ccm, was not returned to the elutant stream, as is often done in these simulated moving bed systems. Thus the ionic components of the feed (essentially sodium chloride) exited from the system via this stream, rather than being recycled to the elutant and ultimately remaining with the purified isosorbide. Isosorbide recovery was in excess of 99%, at a purity of approximately 88%. The operating conditions were not optimized, but one could achieve higher product purity by running at a lower recovery of isosorbide.

During the course of the run no accumulation of solids in the bed were observed. When the feed material to the beds was switched to a solution of crude isosorbide made under standard reaction conditions solids precipitated and accumulated in the beds. The run was stopped and the solids were flushed from the beds using 1 molar sodium hydroxide.

EXAMPLE 6 Chromatographic Separation of Isosorbide after Wiped Film

Evaporation The chromatographic operation need not be applied only to the crude feed that exits the reactor. Wiped film evaporation or similar techniques have been used by us to remove up to 50% of the isosorbide from the feed (usually on material which is neutralized prior to evaporation). Typical conditions for this evaporation are a vacuum level of 29 inches of mercury or more, and jacket temperatures of 120°C or more. The bottoms from such an operation, depleted in isosorbide, are then used as feed to similar chromatographic conditions to those used in processing the crude feed.

Claims

CLAIMS What is claimed is:

1. A process for the recovery of purified isosorbide comprising the steps of separating an isosorbide fraction from a mixture containing isosorbide by chromatography of the mixture, with a suitable solvent or solvent mixture, in the presence of a suitable sorbent, then removing the solvent from the isosorbide product.

2. A process for the recovery of purified isosorbide comprising the steps of: separating an isosorbide fraction from a mixture containing isosorbide by chromatography in the presence of strong-acid cation exchange resin, followed by crystallization of a solution of the recovered fraction.

3. A process for recovering purified isosorbide comprising: (a) distilling isosorbide from an isosorbide feed stream; then

(b) recovering the isosorbide from the distillate bottom via the process of Claim 1.

4. The process of Claim 1 , 2 or 3 wherein the isolated isosorbide product is contacted with activated carbon.

5. The process of Claim 1 , 2, or 3 wherein the isolated isosorbide product is contacted with anion exchange resins.

6. The process for the recovery of high purity isosorbide of Claim 1 comprising the additional step of pretreating the mixture containing isosorbide to remove impurities, before separating the isosorbide fraction by chromatography, wherein the pretreatment is selected from the group consisting of:

(a) prediluting the mixture containing isosorbide with water, precipitating the impurities, and filtering to remove insoluble impurities, then using the filtered product as feed, with or without reconcentration;

(b) pretreating the mixture containing isosorbide with a material such as activated carbon that removes the impurities by adsorption; and

(c) pretreating the mixture containing isosorbide to remove impurities by filtering the mixture through a membrane.

7. The process for the recovery of purified isosorbide of Claim 1 in which the pH of the system is elevated in order to keep byproducts dissolved during the chromatographic process.

8. The process for the recovery of purified isosorbide of Claim 1 in which fresh elutant is used and in which the "recycle" stream is allowed to exit the system, thereby enabling the simultaneous demineralization and purification of the isosorbide.

9. The process of Claim 1 wherein the mixture containing isosorbide is a crude reaction product whereby an isosorbide mixture is produced.

10. The process of Claim 1 wherein the solvent is water.

11. The process of Claim 1 wherein the sorbent is a strong acid ion exchange resin.

12. The process of Claim 11 wherein the size of the sorbent is in the range of 200-500 microns.