Microwave Assisted Synthesis of Dehydrated Sugar Derivatives Hydroxymethylfurfural, Levulinic Acid, Anhydrosugar Alcohols, and E

(19) TZZ _T

(11) EP 2 598 466 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 51/00 (2006.01) C07D 307/02 (2006.01) 28.09.2016 Bulletin 2016/39 C07C 67/00 (2006.01) C07D 307/93 (2006.01) C07D 493/04 (2006.01) C07D 307/46 (2006.01) (2006.01) (2006.01) (21) Application number: 11812946.9 C07D 307/48 C07D 307/50 C07C 59/185 (2006.01) (22) Date of filing: 18.07.2011 (86) International application number: PCT/US2011/044324

(87) International publication number: WO 2012/015616 (02.02.2012 Gazette 2012/05)

(54) MICROWAVE ASSISTED SYNTHESIS OF DEHYDRATED SUGAR DERIVATIVES HYDROXYMETHYLFURFURAL, LEVULINICACID, ANHYDROSUGAR ALCOHOLS, AND ETHERS THEREOF MIKROWELLENUNTERSTÜTZTE SYNTHESE VON DEHYDRIERTEN ZUCKERDERIVATEN, HYDROXYMETHYLFURFURAL, LÄVULINSÄURE, ANHYDROZUCKERALKOHOLEN SOWIE DEREN ETHERN SYNTHÈSE ASSISTÉE PAR RAYONNEMENT MICROONDES DES DÉRIVÉS DE SUCRES DÉSHYDRATÉS HYDROXYMÉTHYLFURFURAL, ACIDE LÉVULINIQUE, ALCOOLS DE SUCRE ANHYDRES ET LEURS ÉTHERS

(84) Designated Contracting States: (74) Representative: dompatent von Kreisler Selting AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Werner - GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Partnerschaft von Patent- und Rechtsanwälten PL PT RO RS SE SI SK SM TR mbB Deichmannhaus am Dom (30) Priority: 30.07.2010 US 369350 P Bahnhofsvorplatz 1 50667 Köln (DE) (43) Date of publication of application: 05.06.2013 Bulletin 2013/23 (56) References cited: WO-A2-2009/155020 US-A- 5 558 899 (73) Proprietor: Archer-Daniels-Midland Company US-A1- 2007 213 544 US-A1- 2007 213 544 Decatur, IL 62526 (US) US-A1- 2009 156 841 US-A1- 2009 156 841 US-A1- 2009 253 920 US-A1- 2009 281 338 (72) Inventors: • HOWARD, Stephen J. • QI X ET AL: "Catalytical conversion of fructose Sherman and glucose into 5-hydroxymethylfurfural in hot Illinois 62684 (US) compressed water by microwave heating", • SANBORN, Alexandra J. CATALYSIS COMMUNICATIONS, ELSEVIER Lincoln SCIENCE,AMSTERDAM, NL, vol. 9, no. 13, 20 July Illinois 62656 (US) 2008 (2008-07-20), pages 2244-2249, XP022824415, ISSN: 1566-7367, DOI: 10.1016/J.CATCOM.2008.04.025 [retrieved on 2008-05-13]

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 598 466 B1

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• XINHUA QI ET AL: "Catalytic dehydration of • THOMAS S. HANSEN ET AL: "Efficient fructose into 5-hydroxymethylfurfural by microwave-assisted synthesis of ion-exchange resin in mixed-aqueous system by 5-hydroxymethylfurfural from concentrated microwave heating", GREEN CHEMISTRY, vol. aqueous fructose", CARBOHYDRATE 10, no. 7, 1 January 2008 (2008-01-01), page 799, RESEARCH, vol. 344, no. 18, 1 December 2009 XP055043574, ISSN: 1463-9262, DOI: (2009-12-01), pages 2568-2572, XP055097102, 10.1039/b801641k ISSN: 0008-6215, DOI: 10.1016/j.carres.2009.09.036

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Description

TECHNICAL FIELD

5 [0001] The present disclosure relates to improved methods of producing the dehydrated sugar derivatives such as 2,5-(hydroxymethyl)furfural ether and ester derivatives, levulinate esters, anhydrosugar alcohols ether and ester derivatives using microwave radiation to catalyze the reactions.

BACKGROUND 10 [0002] The principle sugars from plant materials, glucose and fructose, have been shown to be useful renewable starting materials for the production of a variety of organic compounds that may substitute for petroleum based compounds. For example, the furan compound, 2,5-(hydroxymethyl)furaldehyde, also known as 2,5-(hydroxymethyl)furfural (HMF) a five membered heterocycle obtained by dehydration of a hexose, most efficiently from fructose. 15 [0003] HMF has strong potential in industrial and commercial applications especially for polymer applications due to its multi-functionality which allows for use as a monomer in polymerization reactions.

[0004] Generation of HMF by dehydration of fructose produces three equivalents of water as by products, and the 30 formation of 3 double bonds (two alkenes and one aldehyde). In order to compete as substitutes or replacements in the chemicals market, HMF must be produced at relatively low cost. The production of HMF has been studied for years, but an efficient and cost-effective method of producing HMF has yet to be found. Extended reaction times, high temperatures and pressures cause complications to arise from the rehydration of HMF after the dehydration occurs, which often yields the byproducts of levulinic acid and formic acid. Another competing side reaction is the polymerization of HMF and/or 35 fructose to form humin. [0005] A low yield of HMF is typically obtained when the synthesis is performed in aqueous conditions because of the low selectivity of the dehydration reaction. Low selectivity simultaneously leads to increased polymerization reactions and humin formation, which also interfere with the synthesis of HMF. Where attempts have been made to solve problems associated with aqueous systems, the HMF reaction product is generally sequestered by organic solvent extraction or 40 adsorption onto a resin as soon as it is formed. These systems fail to directly address the issue of low selectivity for HMF. In addition, these systems generally suffer from high dilution or partially irreversible adsorption of HMF and increase cost due to handling and use of the organic solvents or resins. Thus, a selective aqueous reaction system wherein HMF is the predominant product formed at would be desirable. [0006] Levulinic acid is made by dehydration of hexose, which generates HMF as an intermediate, followed by de- 45 formylation resulting in the loss of formic acid. Levulinic acid and levulinate esters have been used as important intermediates in pharmaceutical and fine chemical processes.

[0007] Anhydrosugar alcohols, such as sorbitan and isosorbide derived from glucose, are mono cyclic and bi-cyclic

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ring compounds that are made by the dehydration of 1 or 4 water molecules, respectfully, from a hexitol, which is typically made by hydrogenation of a hexose.

15 [0008] Of all the known isohexides, isosorbide is considered to be one of high importance because of its use in the formation of pharmaceutical compounds, in food production, cosmetic production, plastic and polymer production, and in other potential industrial uses such as in the production of polyurethane, polycarbonate, polyesters, and polyamides (Stoss and Hemmer, 1991). 20 [0009] Several processes for the production of anhydrosugar alcohols (including isohexides such as isosorbide) have been reported. For example, PCT application number PCT/US99/00537 (WO 00/14081), discloses collecting methods and a continuous production method with recycling of organic solvent. Most methods involve the use of concentrated acids and organic solvents. Goodwin et al., Carbohydrate Res. 79:133-141 (1980) have disclosed a method involving the use of acidic-cation-exchange resin in place of concentrated, corrosive acids, but with low yield of isosorbide product. 25 An alternative is the supersaturation-based method, as disclosed in U.S. Pat. No. 4,564,692 (Feldmann, et al., Jan. 14, 1986). However, a need continues for a process for production of very pure dianhydrosugaralcohols, at reasonable yields. [0010] These dehydrated ring derivatives of hexoses, may further be used for making several other compounds, for example, by making ether derivatives of the free alcohol groups as illustrated below:

Where R can be alkyl, allyl,, or aryl 40 [0011] For example, the anhydrosugar alcohol, isosorbide, can be used as a starting material in the formation of isosorbide dimethyl ether and isosorbide dinitrate or as an intermediate in various organic synthesis reactions. Isosorbide dimethyl ether is useful as an industrial solvent, a pharmaceutical additive, and in personal care products, while isosorbide dinitrate is useful as a medication to relieve the pain of angina attacks or reduce the number of such attacks by improving 45 blood flow to the heart. Similar processes are also described in WO 2009/155020 A2; US 2007/0213544 A1; US 2009/0156841 A1; US 2009/0253920 A1; QI X et al., "Catalytical conversion of fructose and glucose into 5-hydroxymethylfurfural in hot compressed water by microwave heating", Catalysis Communications, Elsevier Science, Amsterdam, NL, Vol. 9, No 13, (2008-07-20), pages 2244-2249; Xinhua Qi et al., "Catalytic dehydration of fructose into 5-hydroxymethylfurfural by 50 ionexchange resin in mixed-aqueous system by microwave heating", Green Chemistry, Vol. 10, No. 7, (2008-01-01), page 799 and Thomas S. Hansen et al., "Efficient microwave-assisted synthesis of 5-hydroxymethylfurfural from concentrated aqueous fructose", Carbohydrate Research, Vol. 344. No. 18, (2009-12-01), pages 2568-2572. [0012] Accordingly, there is a need in the art to find methods of making a variety dehydrated sugar compounds and derivatives thereof that is cost effective and efficient. 55 BRIEF SUMMARY

[0013] Methods of producing a variety of dehydrated sugar derivatives are provided. Commonly, for any of the dehy-

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drated sugar derivatives the methods include forming a reaction mixture comprising a solvent and a reactant selected from the group consisting of a hexose, a sugar alcohol, and an anhydrosugar alcohol; and contacting the mixture with microwave radiation bringing it to temperature of between 130°C and 220°C for a time sufficient to convert at least 40% of the reactant into at least one desired dehydrated sugar derivative product, and where in the reaction mixture contains 5 a R-alcohol that is miscible in the reaction mixture, where R is an alkyl, allyl, cycloalkyl, or aryl group, and the desired dehydrated sugar derivative is selected from the group consisting of an R-ether or R-ester of the desired dehydrated sugar derivative and wherein the R-alcohol is the solvent of the reaction mixture. [0014] In another aspect the reactant is a hexose, the reaction mix contains an R -alcohol and the reaction product is an ether of HMF. In a similar aspect, the product is a levulinate ester. Glucose is preferred for making the levulinateesters. 10 In a typical embodiment, the reaction mixture further includes an acid catalyst. [0015] In those aspects where an acidic catalyst may be used, the catalyst is selected from the group consisting of a solid acidsubstrate and a homogeneous acid. In those embodiments where the reactant is a hexose the desired dehydrated sugar derivative is selected from the group consisting of R-oxy HMF, and R acyl-levulinate. [0016] In certain embodiments where reactant is the anhydrosugar alcohol and it is desired to make an ether derivative 15 of the anhydrosugar alcohol, the reaction mixture further contains R-carbonate where R is an alkyl, allyl, cycloalkyl, or aryl group, the solvent is not water, the reaction mixture contains an organic base catalyst, and the desired dehydrated sugar derivative is an R-anhydrosugar alcohol ether. In an exemplary embodiment, isosorbide is the reactant and the dehydrated sugar derivative is mono- or di- R oxy isosorbide. [0017] In most practices greater than 40%, or greater than 50 % of the reactant is converted into the desired dehydrated 20 sugar derivatives. Many embodiments further include at least partially purifying the desired dehydrated derivative from the reaction mixture. In a typical practice, the partial purification includes adding an immiscible organic solvent to the mixture thereby partitioning the dehydrated sugar derivative into immiscible organic solvent solution, collecting the partitioned immiscible organic solvent, and evaporating the collected solvent to produce an extract enriched in the desired dehydrated sugar derivative. Suitable immiscible organic solvent can selected from ethyl acetate, methyl t-butyl ether, 25 diethyl ether, toluene, methyl ethyl ketone, ethyl lactate, methyl isobutyl ketone, octanol, pentanol, butyl acetate, chloroform, and any combinations thereof.

BRIEF DESCRIPTION OF THE DRAWING

30 [0018] Figure 1 is a showing the effect of microwave radiation on the dehydration of sugars in comparison to non- microwave methods.

DETAILED DESCRIPTION

35 [0019] Disclosed herein are methods of improved synthesis of dehydrated sugar derivative ethers and esters. The disclosure is based on the surprising discovery that microwave radiation increases yield and selectivity, while lowering the temperature and time needed to perform dehydration and derivative reactions with sugars. Typically, when used in the presence of a conventional catalyst for such reactions, temperatures in the range of 130 to 180°C can be used for periods of about 30 minutes or less to obtain comparable yields and selectivity obtained at temperatures of 200-250°C 40 using the same reagents and catalyst system without the microwave radiation. Because the temperature is so much lower using the microwave enhance radiations, the catalytic function of the microwave energy must be more than just providing heat to the reaction mixture. Figure 1 shows a direct comparison of total product yields from sugar dehydration using microwave radiation vs non-microwave methods. By microwave radiation, total product yields are enhanced. While not being bound by theory, it is believed that microwave energy preferentially activates the carbon-oxygen-hydrogen 45 bonds involved in dehydration and hydrolytic condensation, thereby facilitate faster dehydration and bond formation at lower energy levels than required by conventional heating. [0020] HMF ethers and esters, and levulinic acid derivatives, such as levulinate esters are provided. Such methods provide the advantages of higher starting concentrations, enhanced reaction rates, high selectivity for the reaction product of choice, ease of manipulation, and precise control over reaction conditions. In certain embodiments, processes are 50 disclosed involving microwave exposure of reactants either in the presence of an aqueous or organic solvent and may be performed with or without a catalyst. [0021] The numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains error necessarily resulting from the standard deviation found in its underlying re- spective testing measurements. Furthermore, when numerical ranges are set forth herein, these ranges are inclusive 55 of the recited range end points ( i.e., end points may be used). When percentages by weight are used herein, the numerical values reported are relative to the total weight. [0022] It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited

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minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10. The terms "one," "a," or "an" as used herein are intended to include "at least one" or "one or more," unless otherwise indicated. [0023] As would be understood in the art, the term "microwave irradiation" refers to electromagnetic waves comprising 5 frequencies of 300 Megahertz (MHz) to 300 Gigahertz (GHz). In certain embodiments, the microwave irradiation range comprises an alternating current signal with a frequency in a range of 300 MHz to 300 GHz. In other embodiments, the microwave irradiation comprises an alternating current signal with a frequency in the range of 300 MHz to 30 GHz. In still other embodiments, the microwave irradiation range comprises an alternating current signal with a frequency in the range of 300 MHz to 3 GHz. 10 [0024] The startingmaterials forthe reactionsdescribed herein are sourcesof sugars and dehydrated sugar derivatives. Examples of sugar sources that may be converted to HMF ethers and levulinic acid esters as well as combinations thereof, include, but are not limited to any source of a sugar, including for example, any hexose, polysaccharides comprising at least one hexose, pentose, corn syrup, a dissolved crystalline fructose, high-fructose corn syrup which is typically a 45 to 75 % wt/wt mixture of fructose with glucose made by isomerization of ordinary corn syrup, high-fructose 15 corn syrup refinery intermediates and by-products such as mother liquor, ordinary corn syrup, which is the glucose syrup obtained from direct hydrolysis of corn starch, process streams from making fructose or glucose, sucrose, sugar cane molasses, and any combinations thereof. The source of the sugar is not important because all sugars will undergo the dehydrations and hydrolytic synthesis reactions to produce the derivatives described herein, however, the reaction products and selectivity of the reactions will of course vary with the particular source of sugar. Where the desired reaction 20 product is a derivative of HMF, it is preferred to use a source that contains larger amounts of fructose. Where the desired reaction product is a levulinic acid ester, the desired starting material should contain larger amounts of glucose. [0025] The reactions provided herein are capable of producing relatively high yields of products. As used throughout the present disclosure herein, "reaction yield" is calculated using the equation (moles of HMF produced/moles of fructose consumed) X 100. Product purity is reported on a weight percent basis. For example, in certain embodiments, greater 25 than 25% of the sugar can be converted to HMF ethers and esters and levulinate esters, as well as combinations thereof. In other embodiments, greater than 50% of the sugar, such as hexose, can be converted to HMF ethers and esters, as well as combinations thereof. In yet other embodiments, greater than 70% or more of the sugar, such as hexose, can be converted to HMF ethers and esters, as well as combinations thereof. [0026] The present disclosure provides various features and aspects of the exemplary embodiments provided herein. 30 It is understood, however, that the disclosure embraces numerous alternative embodiments, which may be accomplished by combining any of the different features, aspects, and embodiments described herein in any combination that one of ordinary skill in the art may find useful. [0027] In certain embodiments, the reaction mixture includes an acid catalyst, Suitable examples of acid catalysts include homogenous acids such as dissolved inorganic acids, soluble organic acids, soluble Brønsted-Lowry acids, and 35 heterogeneous solid acid catalysts, acidic ionexchange resins, acid zeolites, Lewis acids, acidic clays, molecular sieves, and any combinations thereof. In typical embodiments the homogeneous acid may have a range of 0.1 % to 10% by weight starting sugar. In typical embodiments, the homogeneous acid may have a range of 1% to 10% by weight. In other embodiments, the homogeneous acid may have a range of 0.1% to 5% by weight. The heterogeneous solid acid catalysts often comprise a solid material which has been functionalizing to impart acid groups that are catalytically active. 40 Solid acid catalysts may have a broad range of composition, porosity, density, type of acid groups, and distribution of acid groups. Solid acid catalysts may be recovered and reused, optionally with a treatment to regenerate any activity that may have been lost in use. Some solid acid catalysts that may be used include, but are not limited to, Amberlyst 35, Amberlyst 36, Amberlyst 70, Amberlyst 15, Amberlyst 131 (Rohm and Haas, Woodridge, IL), Lewatit S2328, Lewatit K2431, Lewatit S2568, Lewatit K2629 (Sybron Corp, Birmingham, NJ), Dianion SK 104, Dianion PK228, Dianion RCPI60, 45 RCP21H, Relite RAD/F (Mitsubishi Chemical, White Plains, NY), Dowex 50WX4 (Dow Chemical) and any combination thereof. In certain embodiments of the present disclosure, the solid acid catalyst may have a range of 1% to 50% by weight. In some embodiments, the solid acid catalyst may have a range of 1% to 25% by weight. In other embodiments, the solid acid catalyst may have a range of 1% to 10% by weight. [0028] In exemplary embodiments, either a heterogeneous solid acid catalyst like Amberlyst 35 resin, or a homoge- 50 neous acid catalyst exemplified by H2SO4 was used. [0029] Suitable organic solvents which may also be present in the reaction mixture are polar organic aprotic solvents. Examples of possible solvents include, but are not limited to, 1-methyl-2-pyrrolidinone, dimethylacetamide, dimethylfor- mamide, dimethyl sulfoxide, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, and any combinations thereof. 55 [0030] Suitable heterogeneous acids catalysts that may be used include, but are not limited to, Amberlyst 35, Amberlyst 36, Amberlyst 70, Amberlyst 15, Amberlyst 131 (Rohm and Haas, Woodridge, IL), Lewatit S2328, Lewatit K2431, Lewatit S2568, Lewatit K2629 (Sybron Corp, Birmingham, NJ), Dianion SK 104, Dianion PK228, Dianion RCPI60, RCP21H, Relite RAD/F (Mitsubishi Chemical, White Plains, NY), Dowex 50WX4 (Dow Chemical) and any combination thereof. In

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certain embodiments of the present disclosure, the solid acid catalyst may have a range of 1 % to 50% by weight. In some embodiments, the solid acid catalyst may have a range of 1% to 25% by weight. In typical embodiments, the solid acid catalyst is used at a range of 1% to 10% by weight of the starting sugar. [0031] Suitable homogeneous acids that may be used include inorganic acids such as such as H 2SO4, H3PO4, HCl, 5 as well as strong organic acids such as oxalic acid, levulinic acid, and p-toluene sulfonic acid. [0032] Other catalysts not exemplified may also be used. These include, but are not limited to boron trifluoride etherate, and metals, such as Zn, Al, Cr, Ti, Th, Zr, and V. [0033] Although use of an organic solvent and a catalyst is preferred, neither are necessary to obtain suitable yields. The reaction may, for example, be conducted in an aqueous solvent with or without added catalyst. Under aqueous 10 conditionswithout catalyst, the reaction temperature shouldbe brought to about 200-210°C usingthe microwaveradiation, however, the time should be shortened to less than 5 minutes to avoid rehydration and production of levulinic acid and other non selective by-products. [0034] Figure 1 illustrates data from several experiments showing the production and yield. [0035] HMF ethers can also be made directly under similar reaction conditions if fructose is used as the starting material 15 and reaction solvent is an alcohol. Any organic alcohol or alcohol mixture can be used, including allyl, alkyl, aryl, and cycloalkyl alcohols. In most practical embodiments a C1 to C8 alcohol would be used, such as methanol, ethanol, propanols, primary and branched alcohols, and amyl or isoamyl alcohol. [0036] Exemplary HMF ethers, include, but are not limited to, ethoxymethylfurfural, butoxymethylfurfural, isoamyloxyfurfural, and methoxymethylfurfural inter alia or any combination thereof. In addition, the reaction product may, comprise 20 corresponding HMF esters, exemplified, 5-acetoxymethylfurfural, inter alia and any combination thereof. [0037] The reaction mixture preferably contains a catalyst and exemplary catalyst include the same heterogeneous and homogeneous acid catalyst in the same amounts mentioned for HMF synthesis. Typical reaction conditions include irradiating the mixture containing fructose, the catalyst and the alcohol solvent to bring it a temperature of between 140 to about 200°C for a time sufficient to convert at least 50% of the fructose to the HMF ether derivative of the alcohol 25 solvent. Typical reaction times are only 30 minutes or less. Temperatures toward the higher end of the range will lead to production of more HMF ether, but also more levulinic acid ester derivatives than lower temperatures. Thus, for example, when the reaction was conducted at 160°C for 10 minutes in the presence of isoamyl alcohol and2 SOH 4 catalyst, about 16% of the reaction product was to isoamyl levulinate and about 55% was the isoamyloxyfurfural derivative. At 200°C for 30 minutes under the same conditions, about 18% of the reaction product was to isoamyl levulinate but 30 about 59% was the isoamyloxyfurfural derivative. [0038] Levulinic acid esters: To selectively make the levulinic acid ester derivatives, it is preferable to start with a sugar source that contains larger amounts of glucose. Formation of the levulinic acid esters also entails use of the heterogeneous or homogeneous acid catalyst and the solvent again should be, or contain, the same type of alcohols mentioned above from making HMF derivatives. 35 [0039] In typical embodiments, dextrose (glucose obtained by hydrolysis of starch) is combined with the alcohol and acid catalyst and heated to a temperature of between 130 and 200°C by contact with microwave radiation for a period of 15 to 45 minutes to yield a reaction product that is at least 40% levulinate ester. In exemplary embodiments, dextrose in ethanol was combined with a heterogeneous acidic resin (Amberlyst 35) and heated to 170°C for a period of 30 minutes after a temperature ramp-up period of 7 minutes. The product yield was typically about 50 % of ethyl levulinate 40 from dextrose. Smaller side products included HMF at about 12% and the HMF ether derivative, ethoxymethyl furfural at about 25.4% [0040] Exemplary levulinic esters include, but are not limited to, butyl levulinate, ethyl levulinate, and isoamyl levulinate inter alia and any combination thereof. In certain embodiments, reaction yields of levulinate esters can be very high. [0041] Extraction Steps. In certain embodiments, after an aqueous mixture of sugar has been irradiated for a sufficient 45 time to convert at least a portion of the sugar into HMF esters, HMF ethers, and levulinate esters, an immiscible organic solvent may be added to the mixture, which can be filtered or unfiltered, thereby partitioning the HMF derivatives into an organic phase solution; the organic phase solution may be collected; and the solvent may be evaporated, e.g., under a reduced atmospheric pressure, from the organic phase solution to produce an extract enriched with HMF derivatives or levulnic acid derivatives. Examples of organic solvents that may be used include, but are not limited to, ethyl acetate, 50 methyl t-butyl ether, diether ether, toluene, methyl ethyl ketone, ethyl lactate, methyl isobutyl ketone, octanol, pentanol, butyl acetate, chloroform, and any combination thereof. In addition, the aqueous phase may be collected and the unre- acted fructose can be irradiated again to produce HMF derivatives and levulinate esters, or it can be recycled for another purpose disclosed herein or known in the art. [0042] The disclosed extraction method is particularly advantageous, as it eliminates the need for a multi-step purifi- 55 cation process, thereby improving speed and efficiency while reducing costs and waste. The extracted reaction products may then be used as a reactant source for further transformation into a variety of useful derivatives or recrystallized to further increase the purity of the reaction product. [0043] Anhydrosugar alcohol ethers can also be efficiently made from the anhydrosugar alcohols using microwave

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assisted irradiaton. Isosorbide dimethyl ether may be used for various applications including, but not limited to, industrial solvents, pharmaceutical additives, and personal care products. [0044] One aspect of forming ethers from anhydrosugar alcohols is the use of dialkyl carbonates at greatly reduced temperatures pressures, and times. In prior reactions, use of dialkyl carbonates to form the corresponding alkyl ether 5 derivatives of isosorbide required temperatures of 240-260°C, pressures of 4 MPa, and reaction times of two hours or greater. In the present teaching, the reaction can be done by irradiating the mixture with microwaves to temperatures as low as 120-170°C in as little as 10-30 minutes. In an exemplary embodiment using isosorbide and dimethyl carbonate, the microwave power was 1000 watts, the reaction temperature was 150°C with a ramp-up to temperature time of 2 minutes and continued microwave exposure was use to maintain that temperature for only 15 minutes. Any solvent that 10 can dissolve the reactants and products would be suitable so long as sufficient molar amounts of dialkyl carbonate are present. The alkyl group of the dialkyl carbonates can be of any length soluble in the solvent and may comprise aryl, or cycloalkyl or allyl moieties. A base catalyst is preferentially used. One exemplary base catalyst is dimethlyaminopyridine (DMAP). Other bases including non nucleophilic organic bases, sodium methoxide, solid supported bases, basic resins, weak inorganic bases, and strong inorganic bases may also be applied. This method is very beneficial as it increases 15 the selectivity of the reaction. For example, a weak base would increase the product selectivity towards the monoalkylether. Alternatively, if a strong base is used, the dialkylether would be favored. Therefore, the choice of base would allow for more control over the product selectivity. [0045] The various embodiments of the present disclosure may be better understood when read in conjunction with the following examples. 20 EXAMPLES

[0046] The following examples illustrate various non-limiting embodiments of the compositions and methods of the present disclosure and are not restrictive of the invention as otherwise described herein. Unless otherwise indicated, all 25 percentages are by weight. The yields disclosed herein are exemplary and do not reflect the optimal yields under optimized conditions.

EXAMPLE 1

30 PREPARATION OF ISOAMYL HMF

[0047] In a first experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H 2SO4 (0.10 mL) was placed in sealed a Teflon-lined reaction vessel inside a high-density rotor for treatment in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature via microwaves to 200°C in 3 min., and kept 35 there for 3 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 59% molar yield of isoamyl HMF and 18% yield of isoamyl levulinate from fructose. [0048] In the second experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H2SO4 (0.10 mL) was placed in a sealed Teflon-lined reaction vessel inside a high-density rotor for treatment in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature via microwaves to 160°C in 3 min., 40 and kept there for 20 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 61 % molar yield of isoamyl HMF and 27% yield of isoamyl levulinate from fructose. These same conditions, when performed with a conventional heating system, produced 33% molar yield of isoamyl HMF and 24% molar yield of isoamyl levulinate. [0049] In the third experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H2SO4 (0.10 mL) was placed in a sealed Teflon-lined reaction vessel inside a high-density rotor for treatment via micro- 45 waves in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature to 160°C in 3.5 min., and kept there for 10 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 55% molar yield of isoamyl HMF and 16% yield of isoamyl levulinate from fructose.

EXAMPLE 2 50 PREPARATION OF LEVULINATE ESTER

[0050] In a first experiment, a mixture of crystalline dextrose (4 g) in ethanol (40 mL) and dry Amberlyst 35 resin (4 g) was placed in a sealed Teflon-lined reaction vessel inside a high-density rotor for treatment via microwaves in a Mi- 55 croSYNTH Microwave Labstation. The sample was heated from room temperature to 170°C in 7 min. and maintained at this temperature for 30 min. using an irradiation power of 1000 Watts. The vessel was then cooled. Analysis indicated a 49.4% molar yield of ethyl levulinate 12.3% molar yield of HMF and 3% molar yield of ethoxymethylfurfural from dextrose. These same conditions, when performed using conventional heating methods, provided 24% molar yield of

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ethyl levulinate, 9% dextrose, and 2% yield of HMF. [0051] In a second experiment, a mixture of crystalline dextrose (7 g) in ethanol (70 mL) and dry Amberlyst 35 resin (7.02 g) was placed in a sealed Teflon-lined reaction vessel inside a high-density rotor for treatment via microwaves in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature to 170°C in 7 min. and maintained 5 at this temperature for 30 min. using an irradiation power of 1000 Watts. The vessel was then cooled. Analysis indicated a 49.3% molar yield of ethyl levulinate from dextrose. [0052] In a third experiment, a mixture of crystalline dextrose (7 g) in ethanol (70 mL) and dry Amberlyst 35 resin (3.54 g) was place in a sealed Teflon-lined reaction vessel inside a high density rotor for treatment via microwaves in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature to 170°C in 7 min., and kept there 10 for 30 min. using an irradiation power of 1000 Watts. The vessel was then cooled. Analysis indicated a 25.4% molar yield of ethyl levulinate from dextrose.

Claims 15 1. A method of producing a dehydrated sugar derivative comprising,

a. forming a reaction mixture comprising a solvent and a reactant selected from the group consisting of a hexose, a sugar alcohol, and an anhydrosugar alcohol; and 20 b. contacting the reaction mixture with microwave radiation comprising electromagnetic waves with frequencies of 300 MHz to 300 Ghz to achieve a temperature of between 130°C and 210°C for a time sufficient to convert at least 40% of the reactant into at least one desired dehydrated sugar derivative product and

where in the reaction mixture contains a R-alcohol that is miscible in the reaction mixture, where R is an alkyl, allyl, 25 cycloalkyl, or aryl group, and the desired dehydrated sugar derivative is selected from the group consisting of an R-ether or R-ester of the desired dehydrated sugar derivative and wherein the R-alcohol is the solvent of the reaction mixture.

2. The method of claim 1 wherein the reaction mixture further contains an acidic catalyst selected from the group 30 consisting of a heterogeneous solid acid substrate and a homogeneous acid.

3. The method of claim 1 wherein the reactant is a hexose and the desired dehydrated sugar derivative is selected from the group consisting of a HMF ether, and a levulinate ester, in particular when the hexose is glucose, the levulinate ester is the predominant desired dehydrated sugar derivative and when the hexose is fructose, the pre- 35 dominant desired dehydrated sugar derivative is the a HMF ether.

4. The method of claim 3 wherein the acid catalyst is a homogeneous acid and the desired dehydrated sugar derivative is the levulinate ester or the acid catalyst is a solid acid resin and the desired dehydrated sugar derivative is HMF.

40 5. The method of claim 1 wherein the solvent is not water and the reaction temperature is between 130°C and 190°C.

6. The method of claim 1 wherein greater than 50% of the reactant is converted to the desired dehydrated sugar derivative.

45 7. The method of claim 1, further including at least partially purifying the desired dehydrated derivative from the reaction mixture by at least:

adding an immiscible organic solvent to the mixture wherein the immiscible organic solvent is in particular selected from the group consisting of ethyl acetate, methyl t-butyl ether, diethyl ether, toluene, methyl ethyl 50 ketone, ethyl lactate, methyl isobutyl ketone, octanol, pentanol, butyl acetate, chloroform, and any combinations thereof, thereby partitioning the dehydrated sugar derivative into immiscible organic solvent solution; collecting the partitioned immiscible organic solvent ; and evaporating the collected solvent to produce an extract enriched in the desired dehydrated sugar derivative.

55 Patentansprüche

1. Verfahren zur Herstellung eines dehydratisierten Zuckerderivats, umfassend:

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a. Bilden eines Reaktionsgemischs, das ein Lösungsmittel und einen Reaktanten, der aus der Gruppe ausge- wählt ist, die aus einer Hexose, einem Zuckeralkohol und einem Anhydrozuckeralkohol besteht, umfasst; und b. In-Kontakt-Bringen des Reaktionsgemischs mit Mikrowellenstrahlung, die elektromagnetische Wellen mit Frequenzen von 300 MHz bis 300 GHz umfasst, um eine Temperatur zwischen 130 °C und 210 °C während 5 einer ausreichenden Zeit zu erreichen, um wenigstens 40% des Reaktanten zu wenigstens einem erwünschten dehydratisierten Zuckerderivatprodukt umzusetzen; und

wobei das Reaktionsgemisch einen R-Alkohol enthält, der in dem Reaktionsgemisch mischbar ist, wobei R eine Alkyl-, Allyl-, Cycloalkyl- oder Arylgruppe ist und das gewünschte dehydratisierte Zuckerderivat aus der Gruppe 10 ausgewählt ist, die aus einem R-Ether oder R-Ester des gewünschten dehydratisierten Zuckerderivats besteht, und wobei der R-Alkohol das Lösungsmittel des Reaktionsgemischs ist.

2. Verfahren gemäß Anspruch 1, wobei das Reaktionsgemisch weiterhin einen sauren Katalysator enthält, der aus der Gruppe ausgewählt ist, die aus einem heterogenen festen Säuresubstrat und einer homogenen Säure besteht. 15 3. Verfahren gemäß Anspruch1, wobeider Reaktant eineHexose ist und das gewünschtedehydratisierte Zuckerderivat aus der Gruppe ausgewählt ist, die aus einem HMF-Ether und einem Lävulinsäureester besteht, und insbesondere, wenn es sich bei der Hexose um Glucose handelt, der Lävulinsäureester das vorwiegende gewünschte dehydratisierte Zuckerderivat ist und, wenn es sich bei der Hexose um Fructose handelt, das vorwiegende gewünschte 20 dehydratisierte Zuckerderivat ein HMF-Ether ist.

4. Verfahren gemäß Anspruch 3, wobei der saure Katalysator eine homogene Säure ist und das gewünschte dehydratisierte Zuckerderivat der Lävulinsäureester ist oder der saure Katalysator ein festes Säureharz ist und das ge- wünschte dehydratisierte Zuckerderivat HMF ist. 25 5. Verfahren gemäß Anspruch 1, wobei das Lösungsmittel nicht Wasser ist und die Reaktionstemperatur zwischen 130 °C und 190 °C liegt.

6. Verfahren gemäß Anspruch 1, wobei mehr als 50% des Reaktanten in das gewünschte dehydratisierte Zuckerderivat 30 umgewandelt werden.

7. Verfahren gemäß Anspruch 1, weiterhin umfassend das wenigstens partielle Reinigen des gewünschten dehydratisierten Derivats aus dem Reaktionsgemisch, indem man wenigstens:

35 ein unmischbares organisches Lösungsmittel zu dem Gemisch gibt, wobei das unmischbare organische Lö- sungsmittel insbesondere aus der Gruppe ausgewählt ist, die aus Ethylacetat, Methyl-t-butylether, Diethylether, Toluol, Methylethylketon, Ethyllactat, Methylisobutylketon, Octanol, Pentanol, Butylacetat, Chloroform und ir- gendwelchen Kombinationen davon besteht, wodurch das dehydratisierte Zuckerderivat in die Lösung des unmischbaren organischen Lösungsmittels ausgeschüttelt wird; 40 Auffangen des ausgeschüttelten unmischbaren organischen Lösungsmittels; und Verdampfen des aufgefangenen Lösungsmittels, wobei ein Extrakt entsteht, der an dem gewünschten dehydratisierten Zuckerderivat angereichert ist.

45 Revendications

1. Procédé de production d’un dérivé de sucre déshydraté comprenant,

a. la formation d’un mélange réactionnel comprenant un solvant et un réactif choisi dans le groupe consistant 50 en un hexose, un alcool de sucre, et un alcool d’anhydrosucre ; et b. la mise en contact du mélange réactionnel avec un rayonnement microondes comprenant des ondes élec- tromagnétiques avec des fréquences de 300 MHz à 300 GHz pour atteindre une température entre 130 °C et 210 °C pendant une durée suffisante pour convertir au moins 40 % du réactif en au moins un produit dérivé de sucre déshydraté souhaité et 55 où le mélange réactionnel contient un R-alcool qui est miscible dans le mélange réactionnel, où R est un groupe alkyle, allyle, cycloalkyle ou aryle, et .le dérivé de sucre déshydraté souhaité est choisi dans le groupe consistant en un R-éther, ou un R-ester du dérivé de sucre déshydraté souhaité et dans lequel le R-alcool est le solvant du

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mélange réactionnel.

2. Procédé selon la revendication 1, dans lequel le mélange réactionnel contient en outre un catalyseur acide choisi dans le groupe consistant en un substrat acide solide hétérogène et un acide homogène. 5 3. Procédé selon la revendication 1, dans lequel le réactif est un hexose et le dérivé de sucre déshydraté souhaité est choisi dans le groupe consistant en un éther de HMF, et un ester de lévulinate, en particulier lorsque l’hexose est le glucose, l’ester de lévulinate est le dérivé de sucre déshydraté souhaité prédominant et lorsque l’hexose est le fructose, le dérivé de sucre déshydraté souhaité prédominant est l’éther de HMF. 10 4. Procédé selon la revendication 3, dans lequel le catalyseur acide est un acide homogène et le dérivé de sucre déshydraté souhaité est l’ester de lévulinate ou le catalyseur acide est une résine acide solide et le dérivé de sucre déshydraté souhaité est le HMF.

15 5. Procédé selon la revendication 1, dans lequel le solvant n’est pas l’eau et la température de réaction est comprise entre 130 °C et 190 °C.

6. Procédé selon la revendication 1, dans lequel plus de 50 % du réactif est converti en dérivé de sucre déshydraté souhaité. 20 7. Procédé selon la revendication 1, incluant en outre la purification au moins partielle du dérivé de sucre déshydraté souhaité depuis le mélange réactionnel par au moins :

l’ajout d’un solvant organique immiscible au mélange dans lequel le solvant organique immiscible est en par- 25 ticulier choisi dans le groupe consistant en l’acétate d’éthyle, le méthyl t-butyl éther, le diéthyléther, le toluène, la méthyléthylcétone, le lactate d’éthyle, la méthylisobutylcétone, l’octanol, le pentanol, l’acétate de butyle, le chloroforme, et toutes combinaisons de ceux-ci, séparant ainsi le dérivé de sucre déshydraté dans une solution organique immiscible ; la collecte du solvant organique immiscible séparé ; et 30 l’évaporation du solvant collecté pour produire un extrait enrichi en dérivé de sucre déshydraté souhaité.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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