Process for the production of furan derivatives from glucose

Abstract

A process for the production of furan derivatives from D-glucose, wherein A) D-glucose is converted into D-fructose in an enzymatic process, wherein redox cofactors are used and regenerated, whereby, as a result of at least two further enzymatically catalyzed redox reactions proceeding in the same reaction batch, one of the two redox cofactors accumulates in its reduced form and, respectively, the other one in its oxidized form, whereby D-glucose is converted into D-fructose, involving two or more oxidoreductases, and B) D-fructose is converted into furan derivatives,
and the use of furan derivatives produced in this manner.

Claims

1. A method for producing furan derivatives from D-glucose, comprising: A) converting D-glucose to D-Fructose in a multi-step reaction carried out in a reaction mixture comprising, as product-forming reactants, D-glucose, xylose reductase, sorbitol dehydrogenase, and two or more redox cofactors selected from NAD.sup.+/NADH and/or NADP.sup.+/NADPH, and wherein the multi-step reaction comprises: 1) the xylose reductase and NADH or NADPH reducing at least a portion of the D-glucose to D-sorbitol and forming oxidized NAD.sup.+ or NADP.sup.+ in the reaction mixture; and 2) the sorbitol dehydrogenase and NAD.sup.+ or NADP.sup.+ oxidizing at least a portion of the D-sorbitol to D-fructose and forming reduced NADH or NADPH in the reaction mixture; and B) converting at least a portion of the D-fructose formed in A) into one or more furan derivatives selected from hydroxymethylfurfural, 2,5-furan dicarboxylic acid, and polymerization products thereof.

2. The method of claim 1, the multi-step reaction of A) further comprising: 3) regenerating the NADH or NADPH by the NAD.sup.+ or NADP.sup.+ formed in 1) and a first regenerating oxidoreductase and oxidizing a first redox cosubstrate in the reaction mixture; and 4) regenerating the NAD.sup.+ or NADP.sup.+ by the NADH or NADPH formed in 2) and a second regenerating oxidoreductase and reducing a second redox cosubstrate in the reaction mixture.

3. The method of claim 2, wherein the first and second regenerating oxidoreductases are selected from the group consisting of dehydrogenases, reductases, oxidases and catalases.

4. The method of claim 3, wherein the first and second regenerating oxidoreductases are selected from the group consisting of alcohol dehydrogenases, NADH oxidases, hydrogenases, lactate dehydrogenases, formate dehydrogenases, and oxaloacetate-decarboxylating malate dehydrogenases.

5. The method of claim 2, wherein the first cosubstrate is selected from the group consisting of alcohols, 2-propanol, lactic acid, salts of lactic acid, formic acid, salts of formic acid, malic acid, salts of malic acid, and hydrogen.

6. The method of claim 2, wherein the first cosubstrate comprises a (C.sub.4-C.sub.8)-cycloalkanol or a compound of general formula II: ##STR00010## wherein R.sub.2 and R.sub.3 are independently selected from the group consisting of H, (C.sub.1-C.sub.6)-alkyl, wherein alkyl is linear-chain or branched, (C.sub.1-C.sub.6)-alkenyl, wherein alkenyl is linear-chain or branched and contains one to three double bonds, aryl, C.sub.6-C.sub.12-aryl, carboxyl, (C.sub.1-C.sub.4)-carboxyalkyl, cycloalkyl, and C.sub.3-C.sub.8-cycloalkyl.

7. The method of claim 2, wherein the second cosubstrate is selected from the group consisting of pyruvic acid, salts of pyruvic acid, and oxygen.

8. The method of claim 2, wherein the second cosubstrate comprises oxygen or a compound of general formula I: ##STR00011## wherein R.sub.1 is a linear-chain or branched (C.sub.1-C.sub.4)-alkyl group or a (C.sub.1-C.sub.4)-carboxyalkyl group.

9. The method of claim 1, wherein the D-sorbitol formed in A) is not isolated.

10. The method of claim 1, wherein the redox cofactors are provided in soluble form and/or are immobilized onto solids.

11. The method of claim 1, wherein A) proceeds according to the following reaction scheme: ##STR00012##

12. The method of claim 1, wherein A) proceeds according to the following reaction scheme: ##STR00013##

13. The method of claim 1, further comprising isolating the D-fructose formed in A).

14. The method of claim 13, wherein the D-fructose is isolated in crystalline form.

15. The method of claim 13, wherein B) comprises reacting the D-fructose with an acidic catalyst and a solvent.

16. The method of claim 15, wherein the solvent comprises N-methyl-2-pyrrolidone of formula ##STR00014##

17. The method of claim 16, wherein the N-methyl-2-pyrrolidone is used either as a reaction solvent or as a co-solvent.

18. The method of claim 13, wherein B) is performed as a batch method.

19. The method of claim 18, wherein the batch method is performed under microwave heating.

20. The method of claim 13, wherein B) is performed as a continuous method.

21. The method of claim 20, wherein the continuous method is performed under microwave heating.

22. The method of claim 13, wherein B) is performed using at least one acid catalyst selected from the group consisting of a homogeneous acid catalyst, a heterogeneous acid catalyst, a Lewis acid catalyst, and a silica supported ionic liquid phase (SILP) catalyst.

23. The method of claim 22, wherein the acid catalyst is a homogeneous acid catalyst comprising at least one of sulphuric acid or hydrochloric acid.

24. The method of claim 22, wherein the acid catalyst is a heterogeneous acid catalyst comprising at least one of an ion exchanger, montmorillonite, or ion exchange resin.

25. The method of claim 22, wherein the acid catalyst is a Lewis acid catalyst comprising at least one of CrCl.sub.2, AlCl.sub.3 or SiO.sub.2MgCl.sub.2.

26. A method for producing furan derivatives from D-glucose, comprising: A) converting D-glucose to D-Fructose in a multi-step reaction carried out in a reaction mixture comprising, as product-forming reactants, D-glucose, xylose reductase, sorbitol dehydrogenase, and two or more redox cofactors selected from NAD.sup.+/NADH and/or NADP.sup.+/NADPH, and wherein the multi-step reaction comprises: 1) the xylose reductase and NADH or NADPH reducing at least a portion of the D-glucose to D-sorbitol and forming oxidized NAD.sup.+ or NADP.sup.+ in the reaction mixture; 2) the sorbitol dehydrogenase and NAD.sup.+ or NADP.sup.+ oxidizing at least a portion of the D-sorbitol to D-fructose and forming reduced NADH or NADPH in the reaction mixture; 3) regenerating the NADH or NADPH in the reaction mixture by the NAD.sup.+ or NADP.sup.+ formed in 1) and a first regenerating oxidoreductase selected from the group consisting of dehydrogenases, reductases, oxidases and catalases oxidizing a first redox cosubstrate selected from the group consisting of alcohols, 2-propanol, lactic acid, salts of lactic acid, formic acid, salts of formic acid, malic acid, salts of malic acid, hydrogen, (C.sub.4-C.sub.8)-cycloalkanols, and compounds of general formula II: ##STR00015## wherein R.sub.2 and R.sub.3 are independently selected from the group consisting of H, (C.sub.1-C.sub.6)-alkyl, wherein alkyl is linear-chain or branched, (C.sub.1-C.sub.6)-alkenyl, wherein alkenyl is linear-chain or branched and contains one to three double bonds, aryl, C.sub.6-C.sub.12-aryl, carboxyl, (C.sub.1-C.sub.4)-carboxyalkyl, cycloalkyl, and C.sub.3-C.sub.8-cycloalkyl, and wherein the first redox cosubstrate is oxidized; and 4) regenerating the NAD.sup.+ or NADP.sup.+ in the reaction mixture by the NADH or NADPH formed in 2) and a second regenerating oxidoreductase selected from the group consisting of dehydrogenases, reductases, oxidases and catalases reducing a second redox cosubstrate selected from the group consisting of pyruvic acid, salts of pyruvic acid, oxygen, and compounds of general formula I: ##STR00016## wherein R.sub.1 is a linear-chain or branched (C.sub.1-C.sub.4)-alkyl group or a (C.sub.1-C.sub.4)-carboxyalkyl group, and wherein the second redox cosubstrate is reduced; B) isolating the D-fructose formed in A); and C) reacting the D-fructose isolated in B) with an acidic catalyst and a solvent to convert at least a portion of the D-fructose into one or more furan derivatives.

27. The method of claim 26, wherein the first and second regenerating oxidoreductases are selected from the group consisting of alcohol dehydrogenases, NADH oxidases, hydrogenases, lactate dehydrogenases, formate dehydrogenases, and oxaloacetate-decarboxylating malate dehydrogenases.

28. The method of claim 26, wherein A) proceeds according to the following reaction scheme: ##STR00017##

29. The method of claim 26, wherein A) proceeds according to the following reaction scheme: ##STR00018##

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1

(2) shows results in the dehydration of D-fructose in N-methyl-2-pyrrolidone, with sulphuric acid as a catalyst, according to Example 5

(3) FIG. 2 and FIG. 3

(4) show results in the dehydration of D-fructose in N-methyl-2-pyrrolidone, with sulphuric acid as a catalystimplementation in the microwave reactor according to Example 12

(5) FIG. 4 and FIG. 5

(6) show results in the dehydration of D-fructose in N-methyl-2-pyrrolidone, with hydrochloric acid as a catalystimplementation in the microwave reactor according to Example 13

(7) FIG. 6

(8) shows results in the dehydration of D-fructose in N-methyl-2-pyrrolidone, with Montmorillonite KSF as a catalystimplementation in the microwave reactor according to Example 14

(9) FIG. 7

(10) show results in the dehydration of D-fructose in N-methyl-2-pyrrolidone, with hydrochloric acid as a catalystreaction in the flow reactor according to Example 15

(11) FIG. 8

(12) shows a survey of the tested conditions during the dehydration of D-fructose

(13) FIG. 9

(14) shows a schematic reaction set-up for stopped flow microwave reactions and continuous flow reactions for the production of furan derivatives from D-fructose

(15) In the following examples all temperatures are in degrees Celsius ( C.). The following abbreviations are used: EtOAc ethyl acetate FDCA furan dicarboxylic acid h hour(s) HMF 5-hydroxymethylfurfural HPLC high-performance liquid chromatography IPA isopropyl alcohol (2-propanol) LS levulinic acid MeOH methanol NMP N-methyl pyrrolidone (N-methyl-2-pyrrolidone) PET polyethylene terephthalate PEF polyethylene furanoate RT room temperature SILP Supported Ionic Liquid Phase TFA trifluoroacetic acid

Example 1

Conversion of D-Glucose into D-Fructose Via a Xylose Reductase and a Sorbitol Dehydrogenase, Using an Alcohol Dehydrogenase for Recycling the NADPH and a Lactate Dehydrogenase for Recycling the NAD+

(16) A 0.5 ml batch contains 50 mg/ml D-glucose and 6 U/ml of recombinant xylose reductase from Candida tropicalis (overexpressed in E. coli BL21 (DE3)) and 0.1 mM NADP.sup.+. For the regeneration of the cofactor, 7% (v/v) IPA and 6 U/ml of recombinant alcohol dehydrogenase from Lactobacillus kefir (overexpressed in E. coli BL21 (DE3)) are added. The enzymes are used in the form of cell lysates. The reaction takes place for 24 h at 40 C. and pH=9 (50 mM Tris HCl-buffer) in an open system, with continuous shaking (900 rpm). The open system leads to the removal of the acetone formed, which drives the reaction toward the formation of D-sorbitol. In the open system, water and IPA evaporate too, so that they are additionally dosed in after 6 h and after 21 h. Thereby, at each time, a total volume of 0.5 ml as well as an IPA concentration of 7% (v/v) are again adjusted. After 24 h, the reaction vessel is incubated at 60 C. under vacuum in order to inactivate the enzymes and to evaporate the organic solvents. After cooling to RT, the recombinant D-sorbitol dehydrogenase from Bacillus subtilis (overexpressed in E. coli BL21 (DE3)) is added at a final concentration of 5 U/ml, ZnCl.sub.2 at a final concentration of 1 mM and NAD.sup.+ at a final concentration of 0.1 mM. For cofactor regeneration, 5 U/ml (final concentration) of lactate dehydrogenase from rabbit muscles (Sigma Aldrich) and 300 mM pyruvate are used. The batch is topped up to 0.5 ml with water. The reaction takes place for further 24 h at 40 C. in a closed system with continuous shaking (900 rpm). A conversion of D-glucose into D-fructose of >90% is achieved.

Example 2

Conversion of D-Glucose into D-Fructose Via a Xylose Reductase and a Sorbitol Dehydrogenase, Using an Alcohol Dehydrogenase for Recycling the NADPH and an Oxidase for Recycling the NAD+

(17) A 0.5 ml batch contains 50 mg/ml D-glucose, 6 U/ml of recombinant xylose reductase from Candida tropicalis (overexpressed in E. coli BL21 (DE3)) and 0.1 mM NADP.sup.+. For the regeneration of the cofactor, 7% (v/v) IPA and 6 U/ml of recombinant alcohol dehydrogenase from Lactobacillus kefir (overexpressed in E. coli BL21 (DE3)) are added. The enzymes are used in the form of cell lysates. The reaction takes place for 24 h at 40 C. and pH=8 (50 mM Tris HCl buffer) in an open system, with continuous shaking (900 rpm). The open system leads to the removal of the nascent acetone, which drives the reaction toward the formation of D-sorbitol. In the open system, water and IPA evaporate, too, so that they are additionally dosed in after 6 h and after 21 h. Thereby, at each time, a total volume of 0.5 ml as well as an IPA-concentration of 7% (v/v) are again adjusted. After 24 h, the reaction vessel is incubated at 60 C. under vacuum in order to inactivate the enzymes and to evaporate IPA as well as any acetone that has formed. After cooling to room temperature, the recombinant D-sorbitol dehydrogenase from Bacillus subtilis (overexpressed in E. coli BL21 (DE3)) is added at a final concentration of 5 U/ml, CaCl.sub.2 at a final concentration of 1 mM and a mixture (1:1) of NAD.sup.+ and NADH at a final concentration of 0.1 mM. For cofactor regeneration, 10 U/ml (final concentration) of NADH oxidase from Leuconostoc mesenteroides (overexpressed in E. coli BL21 (DE3)) is used. The enzymes are used in the form of cell lysates. The batch is topped up to 0.5 ml with water. The reaction takes place for another 24 h at 40 C. in an open system, with continuous shaking (900 rpm), in order to ensure sufficient oxygen supply for the NADH oxidase from the air. In that open system at 40 C. water evaporates. Thus, after 6 h and after 21 hit is filled up with water to a volume of 0.5 ml. A conversion of D-glucose into D-fructose of approx. 98% is achieved.

Example 3

Reprocessing and Analytics of Sugars

(18) The batch is incubated at 65 C. for 10 min for inactivating the enzymes and is subsequently centrifuged. The supernatant is then filtered over a 0.2 M PVDF filter and analyzed by ligand-exchange HPLC (Agilent Technologies Inc.). In doing so, sugars and polyols are separated via a lead column of Showa Denko K.K. (Shodex Sugar SP0810) with a flow of 0.5 ml/min water (VWR International GmbH, HPLC Grade) at 80 C. Detection occurs with the aid of a light-refraction detector (RID, Agilent 1260 Infinity, Agilent Technologies Inc.). An inline filter of Agilent Technologies Inc. and, as precolumns, an anion-exchange column (Shodex Axpak-WAG), a reversed-phase column (Shodex Asahipak ODP-50 6E) and a sugar precolumn (SUGAR SP-G), in each case from Showa Denko K.K., are used.

Example 4

Materials and Methods for the Conversion of D-Fructose into Furan Derivatives

(19) In the context of this invention, dehydration reactions of D-fructose into HMF were performed under various reaction conditions, optionally as a standard batch process, with microwave-assisted heating or using continuous flow conditions. FIG. 8 shows a survey of the tested conditions. Surprisingly, it has been found that NMP as a solvent yields higher turnovers in the reaction compared to hitherto known systems, in combination with homogeneous or heterogeneous catalysts both in the microwave-assisted method and under continuous flow conditions.

(20) Synthesis of SiO.sub.2MgCl.sub.2

(21) SiO.sub.2MgCl.sub.2 was produced according to a provision by Yasuda et al. (Yasuda, M.; Nakamura, Y.; Matsumoto, J.; Yokoi, H. Shiragami, T. Bull. Chem. Soc. Jpn. 2011, 84, 416-418).

(22) Synthesis of SILPs

(23) The SILP catalyst was produced in accordance with known provisions (Fu, S.-K.; Liu, S.-T. Synth. Commun. 2006, 36, 2059-2067) by using N-methyl imidazol. For immobilization, the obtained ionic liquid was mixed with 200% by weight of silica gel in dry chloroform (100 mL pro 10 g SiO.sub.2) and heated to 70 C. for 24 h. The obtained solid was filtered off, washed with chloroform and dried under reduced pressure. The silica gel obtained exhibited a load of approx. 16% by weight of a catalyst.

(24) General Conditions Batch Reactions

(25) Unless specified otherwise, all batch reactions were performed in a 4 mL screw lid jar. Heating to the desired temperature was effected in appropriate aluminium blocks.

(26) Microwave Reactions in a Batch Process

(27) In the batch process, microwave reactions were performed on a Biotage-Initiator Sixty laboratory microwave equipped with an autosampler in order to enable sequential reaction regimes. The absorption level was adjusted to a maximum value, whereby the maximum energy supply was automatically set to 400 W.

(28) Stopped Flow Microwave Reactions and Continuous Flow Reactions

(29) Stopped flow reactions for optimizing a semi-continuous process management were performed on a CEM Discover System with CEM Voyager Upgrade and by means of an external pressure sensor. For reactions with continuous process management, a cartridge-based reactor system X-Cube from ThalesNano equipped with a Gilson GX-271 Autosampler for automatic product gathering was used. Thereby, two quartz sand cartridges (CatCart, 704 mm) were incorporated as a reaction zone.

(30) Alternatively, a perfluoroalkoxy alkane capillary was used (PFA capillary, inner diameter of 0.8 mm, outer diameter of 1.6 mm), which was wound around a heatable aluminium cylinder. The substrates were added at a desired flow rate by means of a Shimadzu LC-10AD HPLC pump. Exact volumes (column 16.0 mL; dead volume before and after the column, in each case, 1.0 mL) were determined by tracing defined flow rates of the pure solvent with a digital time clock. The reaction set-up is illustrated in FIG. 9.

(31) Analysis of the Reactions for the Conversion of D-Fructose into Furan Derivatives

(32) For a quantitative HPLC analysis, samples of the reaction samples (22 L, unless specified otherwise) were diluted to 1 mL with deionized water. In reaction samples exhibiting a different concentration, the dilution was adjusted such that the maximum concentration did not exceed 2 mg/ml.

(33) 100 L of 3-hydroxybenzyl alcohol were added to said solution as an internal standard, whereupon the sample was mixed thoroughly. Solid residues were separated by centrifugation (5 min, 20000 G) or filtration (Phenex PTFE, 4 mm, 0.2 m). Quantification was effected on the basis of the areas of the peaks in the RI-spectrum in comparison to the internal standard. The samples were analyzed via HPLC on a Thermo Scientific Surveyor Plus System or a Shimadzu Nexera System, each equipped with PDA Plus- and RI detectors. For the separation, an ion exclusion column from Phenomenex (Rezex RHM-Monosaccharide H+ (8%), 1507.8 mm, composed of a crosslinked matrix of sulfonated styrol and divinylbenzol, H.sup.+-form) was used as a stationary phase, and a solvent mixture of water (HPLC-grade) and 0.1% TFA (HPLC-grade) was used as an eluent. The column temperature was kept constant and at 85 C., while the running time was optimized to 25 minutes. Product quantification was performed based on an internal standard by integrating the RI signal. Via PDA, the wavelengths 200 nm, 254 nm and 280 nm were additionally recorded for a further reaction analysis.

(34) GP1D-Fructose Dehydration in a Batch Process

(35) In a standard reaction for optimizing the reaction, 100 mg of D-fructose (0.56 mmol) and the respective catalyst were placed in a desired amount into a glass vial and mixed with 1 mL of freshly distilled NMP. The obtained solution/suspension was heated to the chosen temperature and allowed to react for the desired time.

(36) GP2D-Fructose Dehydration in a Microwave Batch Process

(37) In a standard reaction for optimizing the reaction, 100 mg of D-fructose (0.56 mmol) and the respective catalyst were placed in a desired amount into a microwave vessel (0.5-2.0 mL). The vessel was equipped with a magnetic stirring bar and filled up with 1 mL NMP. The radiation intensity of the microwave was adjusted automatically by a company-owned regulation algorithm in order to reach the desired temperature. Rapid cooling of the reaction vessel was realized with pressurized air of at least 6 bar which was injected.

(38) GP 3D-Fructose Dehydration in a Microwave Stopped Flow Process

(39) In a standard reaction for optimizing the reaction, a D-fructose standard solution (1 mL; c=100 mg/mL in NMP) and hydrochloric acid (100 L; c=1 mol/L) were filled into a microwave vessel and equipped with a magnetic stirring bar. After sealing the vial with a Snap-Cap, the solution was heated to the desired temperature for the desired time. In order to effect the fastest possible heating, the supplied energy was adjusted according to the following Table 1.

(40) TABLE-US-00002 TABLE 1 Power adjustment of the microwave and associated temperatures temperature power adjustment 100 C. 50 W 125 C. 65 W 150 C. 100 W 180 C. 125 W 200 C. 140 W 220 C. 160 W

(41) Rapid cooling of the reaction vessel was realized with pressurized air of at least 6 bar which was injected.

(42) GP4D-Fructose Dehydration in a Cartridge-Based Reactor System

(43) In a standard reaction for optimizing the reaction, a D-fructose standard solution (1 mL; c=100 mg/mL in NMP) was mixed with hydrochloric acid (c=1 mol/L) and pumped into the reaction system through a reagent pump. During the heating process, several preliminary samples were taken in order to monitor a stable temperature and a stable flow rate. 150 C., 180 C. and 200 C. were chosen as reaction temperatures, whereas the reaction pressure was set to 40 bar. For this purpose, flow rates of between 0.2 and 0.6 ml/min were chosen. Reaction samples were collected in amounts of 2.5 mL and analyzed.

Example 5

Use of Sulphuric Acid as a Catalyst for the Dehydration of D-Fructose

(44) Different temperatures, reaction times and acid concentrations were compared. The reactions were performed according to GP1 (Example 4). Either 100 l of 1 N sulphuric acid or 10 l of concentrated sulphuric acid was used as a catalyst. In Table 2, the results are summarized.

(45) TABLE-US-00003 TABLE 2 Sulphuric acid as a catalyst for the dehydration of D-fructose temper reaction fructose HMF HMF LS catalyst ature time consumption yield selectivity yield 1N H.sub.2SO.sub.4 100 C. 3 h 69% 45% 65% <1% 1N H.sub.2SO.sub.4 120 C. 4 h 95% 77% 81% <1% 1N H.sub.2SO.sub.4 150 C. 15 min 98% 88% 90% <1% 1N H.sub.2SO.sub.4 180 C. 10 min 100% 85% 85% <1% H.sub.2SO.sub.4 120 C. 45 min 98% 85% 90% <1% conc. H.sub.2SO.sub.4 150 C. 10 min 100% 90% 90% <1% conc. H.sub.2SO.sub.4 180 C. 5 min 100% 82% 82% <1% conc.

(46) A formation of black insoluble polymers and humines was not observed under the optimum conditions which were employed. For analyzing the course of the reaction, a time series for a representative reaction was included (H.sub.2SO.sub.4 conc., 150 C., see FIG. 1).

Example 6

Use of Chrome-(II)-Chloride as a Catalyst for the Dehydration of D-Fructose

(47) As described by Zhao, H.; Holladay, J. E.; Brown, H.; Zhang, Z. C. Science 2007, 316, 1597-1600, chrome-(II)-chloride may be used as an effective catalyst for the dehydration of D-fructose. In said example, the effect CrCl.sub.2 in N-methyl-2-pyrrolidone is shown. The experiments were conducted according to Provision GP1 (Example 4). While relatively low yields of HMF were achieved, significant amounts of tar-like compounds could be observed (Table 3).

(48) TABLE-US-00004 TABLE 3 Chrome-(II)-chloride as a catalyst for the dehydration of D-fructose amount of reaction fructose HMF HMF LS catalyst temp. time consumption yield selectivity yield 10 mg CrCl.sub.2 100 C. 3 h 86% 51% 59% <1% 10 mg CrCl.sub.2 150 C. 3 h 100% 39% 39% <1%

Example 7

Use of Montmorillonite KSF as a Catalyst for the Dehydration of D-Fructose

(49) 100 mg of D-fructose was incubated in the presence of 1 ml N-methyl-2-pyrrolidone while being stirred (Provision GP1, Example 4). 3 h was consistently chosen as the reaction time. In doing so, different amounts of Montmorrilonite KSF were added as a catalyst. Table 4 summarizes the results. Under the best conditions, an HMF yield of 61% with an HMF selectivity of 63% could be achieved.

(50) TABLE-US-00005 TABLE 4 Montmorillonite KSF as a catalyst for the dehydration of D-fructose fructose HMF HMF LS catalyst temp. consumption yield selectivity yield tar 1 mg 120 C. 37% 11% 31% <1% no 3 mg 120 C. 54% 20% 38% <1% no 5 mg 120 C. 65% 30% 46% <1% no 7 mg 120 C. 73% 32% 44% <1% no 10 mg 120 C. 80% 41% 52% <1% no 20 mg 120 C. 90% 43% 48% <1% no 40 mg 120 C. 94% 43% 46% <1% no 1 mg 130 C. 31% 11% 35% <1% no 3 mg 130 C. 73% 35% 48% <1% no 5 mg 130 C. 87% 46% 53% <1% no 7 mg 130 C. 92% 50% 55% <1% no 10 mg 130 C. 94% 49% 52% <1% no 20 mg 130 C. 96% 54% 57% <1% no 40 mg 130 C. 97% 54% 55% <1% yes 1 mg 140 C. 72% 30% 42% <1% no 3 mg 140 C. 91% 46% 51% <1% no 5 mg 140 C. 95% 53% 56% <1% no 7 mg 140 C. 96% 53% 55% <1% no 10 mg 140 C. 98% 55% 56% <1% no 20 mg 140 C. 98% 56% 57% <1% no 40 mg 140 C. 99% 56% 56% <1% yes 1 mg 150 C. 94% 44% 46% <1% no 3 mg 150 C. 96% 52% 54% <1% no 5 mg 150 C. 98% 56% 57% <1% no 7 mg 150 C. 98% 57% 59% <1% no 10 mg 150 C. 98% 58% 59% <1% yes 20 mg 150 C. 97% 61% 63% <1% yes 40 mg 150 C. 97% 61% 63% <1% yes

Example 8

Use of Amberlite 150 as a Catalyst for the Dehydration of D-Fructose

(51) This example shows the use of a strong ion exchanger with sulfonic acid residues based on a macro-crosslinked resin. 100 mg of D-fructose were incubated in the presence of 1 ml N-methyl-2-pyrrolidone at 100 C. for 3 h, while being stirred (Provision GP1, Example 4). Amberlite 15 was thereby added as a catalyst. In Table 5, the result of said experiment is shown. In contrast to Montmorillonite KSF, a higher yield could be obtained at the relatively low temperature. The formation of tar-like compounds was avoided.

(52) TABLE-US-00006 TABLE 5 Amberlite 15 as a catalyst for the dehydration of D-fructose amount of reaction fructose HMF HMF LS catalyst temp. time consumption yield selectivity yield 10 mg 100 C. 3 h 70% 50% 71% <1%

Example 9

Use of SiO2MgCl2 as a Catalyst for the Dehydration of D-Fructose

(53) Since a silica gel-magnesium chloride-complex displayed a catalytic activity during the dehydration of carbohydrates in acetonitrile (Yasuda, M.; Nakamura, Y.; Matsumoto, J.; Yokoi, H. Shiragami, T. Bull. Chem. Soc. Jpn. 2011, 84, 416-418), said catalyst was tested for its suitability in N-methyl-2-pyrrolidone. Under reaction conditions as in GP1 (Example 4), a yield of 26% HMF was achieved in the best case (see Table 6). However, if merely a silica gel was used, the yield fell to below 1%. The formation of large amounts of tar-like compounds was thereby observed.

(54) TABLE-US-00007 TABLE 6 SiO.sub.2MgCl.sub.2 as a catalyst for the dehydration of D-fructose amount of reaction fructose HMF HMF LS catalyst temp. time consumption yield selectivity yield 200 mg 150 C. 30 min 99% 26% 26% 4%

Example 10

Use of AlCl3 as a Catalyst for the Dehydration of D-Fructose

(55) AlCl.sub.3 was tested under reaction conditions GP1 (Example 4) as an example of a Lewis acid catalyst. Freshly sublimated AlCl.sub.3 was used for this purpose. Similar results as with Amberlite 15 were achieved. However, the catalyst is sensitive to hydrolysis and thus cannot be used for repeated applications or in continuous processes. In addition, relatively large amounts of tar-like compounds were formed (for the result, see Table 7).

(56) TABLE-US-00008 TABLE 7 AlCl.sub.3 as a catalyst for the dehydration of D-fructose amount of reaction fructose HMF HMF LS catalyst temp. time consumption yield selectivity yield 10 mg 100 C. 3 h 100% 50% 50% <1%

Example 11

Use of SILPs Combined with Chrome-(II)-Chloride as a Catalyst for the Dehydration of D-Fructose

(57) A combination of CrCl.sub.2 and SILPs (silica-supported ionic liquid phase, see Example 4) was tested, wherein the reaction conditions GP1 (Example 4) were applied. After 20 min, a yield of almost 50% HMF could be achieved. This, however, could not be increased with longer reaction times. Furthermore, a conversion of D-fructose into D-glucose could be detected with shorter reaction times (Table 8).

(58) TABLE-US-00009 TABLE 8 SILPs combined with CrCl.sub.2 as a catalyst for the dehydration of D-fructose reaction fructose glucose HMF HMF LS temp. time consumption yield yield selectivity yield 120 C. 5 min 85% 5% 39% 46% <1% 120 C. 10 min 94% 3% 45% 48% <1% 120 C. 15 min 99% 1% 44% 45% <1% 120 C. 20 min 97% 2% 49% 51% <1% 120 C. 25 min 97% 1% 47% 48% <1% 120 C. 30 min 98% <1% 49% 50% <1% 120 C. 45 min 99% <1% 48% 49% <1% 120 C. 1 h 99% <1% 52% 52% <1%

Example 12

Use of Sulphuric Acid as a Catalyst for the Dehydration of D-Fructose (Microwave Heating)

(59) In order to achieve a better control over the heating phase and the cooling phase as well as over the reaction temperature, a microwave-based system was used for adjusting the temperature. Using N-methyl-2-pyrrolidone, samples were prepared as specified in ProvisionGP2 (Example 4). No formation of tar-like compounds was detected under the reaction conditions which were applied. A complete conversion of D-fructose and a yield of 83% HMF could maximally be achieved (FIG. 2 and FIG. 3).

Example 13

Use of Hydrochloric Acid as a Catalyst for the Dehydration of D-Fructose (Microwave Heating)

(60) The dehydration of D-fructose was performed in a stopped-flow microwave reactor according to Provision GP3 (Example 4). Higher temperatures were necessary for achieving a complete conversion of D-fructose. While, at lower temperatures, longer reaction times improved the yield of HMF, the latter decreased at higher temperatures with an increasing reaction time (FIGS. 4 and 5). With a complete conversion of D-fructose, a maximum yield of 89% HMF could be achieved.

Example 14

Use of Montmorillonite KSF as a Catalyst for the Dehydration of D-Fructose (Microwave Heating)

(61) Since a rapid heating/cooling as well as a very good control of the temperature in the reaction vessel can be effected with microwave methods, the heterogeneous catalyst Montmorillonite KSF was also used for the dehydration of D-fructose in N-methyl-2-pyrrolidone. Reaction conditions according to GP2 (Example 4) were employed. The reaction time amounted to 5 min. Although only comparatively low D-fructose conversions and HMF yields were achieved, the formation of tar-like compounds could be avoided (for the results, see Table 9).

(62) TABLE-US-00010 TABLE 9 Montmorillonite KSF as a catalyst for the dehydration of D-fructose (microwave heating) amount of fructose HMF HMF LS catalyst temp. consumption yield selectivity yield tar 5 mg 150 C. 51% 20% 39% <1% no 7 mg 150 C. 61% 26% 43% <1% no 10 mg 150 C. 64% 30% 46% <1% no 15 mg 150 C. 76% 38% 50% <1% no 20 mg 150 C. 82% 43% 52% <1% no

(63) In order to find the best reaction conditions, different reaction times were tested at 150 C., using 20 mg of a catalyst (FIG. 6).

Example 15

Use of Sulphuric Acid for Catalyzing the Conversion of D-Fructose into Furan Derivatives (Continuous Process)

(64) D-Fructose (10% w/v) and concentrated sulphuric acid (1% v/v) were dissolved in N-methyl-2-pyrrolidone. The mixture was pumped through the reactor by means of a PFA capillary with a continuous flow (reaction temperature 150 C.). After the first 18 ml had been discarded, another 10 ml was collected for the analysis. By way of a number of flow rates, the effect of different residence times in the reactor was tested (Table 10).

(65) TABLE-US-00011 TABLE 10 Sulphuric acid for catalyzing the conversion of D-fructose into furan derivatives (continuous process) flow rate residence fructose HMF HMF LS (ml/min) time consumption yield selectivity yield 0.8 ml/min 20 min 100% 74% 74% <1% 1.6 ml/min 10 min 100% 75% 75% <1% 3.2 ml/min 5 min 100% 76% 76% <1%

(66) No formation of black insoluble polymers and humines was observed under the tested conditions.

Example 16

Use of Hydrochloric Acid for Catalyzing the Conversion of D-Fructose into Furan Derivatives (Continuous Process)

(67) In that example, hydrochloric acid was used as a catalyst for the dehydration of D-fructose in NMP under a continuous flow (for the reaction conditions, see Provision GP4, Example 4). A maximum yield of 75% HMF could be achieved at a reaction temperature of 180 C. and a flow of 0.6 ml/min. A selectivity of 76% HMF was thereby achieved. In most cases, the proportion of levulinic acid (LS) was below 1% (for the results, see FIG. 7).