(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`21 December 2007 (21.12.2007)
`
`(10) International Publication Number
`
`WO 2007/146636 A1
`
`(51) International Patent Classification:
`C07D 307/46 (2006.01)
`C07D 307/36 (2006.01)
`C07D 307/08 (2006.01)
`C07D 307/42 (2006.01)
`
`(21) International Application Number:
`PCT/US2007/070313
`
`(22) International Filing Date:
`
`4 Juue 2007 (04.06.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`60/811,343
`
`English
`
`English
`
`6 June 2006 (06.06.2006)
`
`US
`
`(71) Applicant (for all designated States except US): VVIS-
`CONSIN ALUMNI RESEARCH FOUNDATION
`
`[US/US]; 614 Walnut Street, Madison, WI 53707-7365
`(US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): DUMESIC, James,
`A. [US/US]; 3402 Sugar Maple Lane, Madison, WI 53717
`(US). ROMAN-LESHKOV, Yuriy [MX/US];
`3009
`University Avenue, Apt. 306, Madison, VVI 53714 (US).
`CHHEDA, Juben, N. [IN/US]; 4701 Sheboygan Avenue,
`Apt. 104, Madison, WI 53705 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE. AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(74) Agents: LEONE, Joseph, T. et al.; DeWitt Ross &
`Stevens S.C., 8000 Excelsior Drive, Suite 401, Madison,
`WI 53717-1914 (US).
`
`For two—letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations ” appearing at the beg in-
`ning of each regular issue of the PCT Gazette.
`
`V-4
`
`(54) Title: CATALYTIC PROCESS FOR PRODUCING FURAN DERIVATIVES FROM CARBOHYDRATES IN A BIPHASIC
`REACTOR
`
`4 wMeoe
`
`r
`V-1E
`l\
`
`ce
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`(‘I (57) Abstract: Described is a catalytic process for converting sugars to furan derivatives (e. g. 5—hydroxymethylfurfura1, furfural,
`dimethylfuran, etc.) using a biphasic reactor containing a reactive aqueous phase and an organic extracting phase. The process
`provides a cost—effective route for producing di—substituted furan derivatives. The furan derivatives are useful as value—added inter-
`mediates to produce polymers, as precursors to diesel fuel, and as fuel additives.
`
`Petitioners‘ Exhibit 1016, Page 1 of 66
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`Petitioners' Exhibit 1016, Page 1 of 66
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`WO 2007/146636
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`PCT/US2007/070313
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`CATALYTIC PROCESS FOR PRODUCING FURAN DERIVATIVES FROM CARBOHYDRATES IN A
`BIPHASIC REACTOR
`
`James A. Dumesic
`
`Yuriy Roman-Leshkov
`Juben N. Chheda
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`Priority is hereby claimed to provisional application Serial No. 60/811,343, filed
`
`June 6, 2006, which is incorporated herein by reference.
`
`FEDERAL FUNDING STATEMENT
`
`This invention was made with United States government support awarded by the
`
`following agencies: USDA/CSREES 2003-35504-13752 and NSF 0456693. The United
`
`States has certain rights in this invention.
`
`FIELD OF THE INVENTION
`
`The invention is directed to a process for selectively dehydrating carbohydrates,
`
`(preferably sugars, e. g., fructose, glucose, xylose) to yield furan derivatives such as
`
`5-hydroxymethylfurfural (HMF) and furfural. Particularly advantageous is that the
`
`process operates at high sugar concentrations in the reactant feed (preferably from about
`
`10 to about 50 wt%), achieves high yields (> 80% HMF selectivity at 90% sugar
`
`conversion when using fructose as the reactant), and delivers the furan derivative in a
`
`separation-friendly solvent. The process uses a two-phase reactor system wherein the
`
`sugar is dehydrated in an aqueous phase (preferably using an acid catalyst such as HC1 or
`
`an acidic ion-exchange resin). The furan derivative product is continuously extracted
`
`into an organic phase (preferably 1-butanol) thus reducing side reactions.
`
`BACKGROUND
`
`Since at least as early as the mid-1960’s, scientific and economic forecasters have
`
`been predicting an approaching era of diminishing availability of petrochemical resources
`
`to produce the energy and chemical materials needed by industrialized societies. On one
`
`hand, discoveries of new petroleum reserves and new petroleum production technologies
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`Petitioners‘ Exhibit 1016, Page 2 of 66
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`Petitioners' Exhibit 1016, Page 2 of 66
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`(e. g., deep-water, off-shore drilling) have staved off an economically catastrophic
`
`shortage of crude oil. On the other hand, rapidly industrializing national economies
`
`(most notably China and India), coupled with political instability in petroleum-producing
`
`regions (most notably the middle east, Nigeria, and Venezuela), have pushed oil prices to
`
`record levels. In early 2006, the price of a barrel of crude oil topped $70 for the first time
`
`in history. Environmental, ecological, and political considerations have also effectively
`
`made certain proven reserves of petroleum off-limits to commercial exploitation. For
`
`example, production of petroleum from proven reserves in the Artic National Wildlife
`
`Refuge in Alaska has been (and for the foreseeable future, will continue to be) blocked by
`
`federal and state legislation to preserve this unique natural landscape from human
`
`encroachment.
`
`The rippling effect of high crude oil prices on national economies is profound.
`
`Not only are gasoline and diesel the principal transportation fuels worldwide, crude
`
`petroleum also yields a vast array of chemicals that are feedstocks for an equally vast
`
`array of products, from plastics to pesticides. Thus, high crude oil prices spur worldwide
`
`inflation as producers pass on their increased costs of production to consumers.
`
`The economic difficulties caused by increasing demand coupled with diminishing
`
`supply is driving efforts to develop alternative and sustainable ways to meet energy and
`
`raw material needs. The Roadmap for Biomass Technologies in the United States (U.S.
`
`Department of Energy, Accession No. ADA436527, December 2002), authored by 26
`
`leading experts, has predicted a gradual shift from a petroleum-based economy to a more
`
`carbohydrate dependent economy. This official document predicts that by 2030, 20% of
`
`transportation fuel and 25% of chemicals consumed in the United States will be produced
`
`from biomass. Such a shift away from petroleum-based technologies requires developing
`
`innovative, low-cost separation and depolymerization processing technologies to break
`
`down the highly oxygen-functionalized, polysaccharide molecules found in raw biomass,
`
`to yield useful bio-derived materials and fuels. In short, abundant biomass resources can
`
`provide alternative routes for a sustainable supply of both transportation fuels and
`
`valuable intermediates (e. g., alcohols, aldehydes, ketones, carboxylic acid, esters) for
`
`production of drugs and polymeric materials. However, unless these alternative routes
`
`can be implemented at a production cost roughly comparable to the corresponding
`
`Petitioners‘ Exhibit 1016, Page 3 of 66
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`Petitioners' Exhibit 1016, Page 3 of 66
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`production cost when using petroleum feedstocks, the transition will inevitably be
`
`accompanied by severe economic dislocations. It is not enough that the transition can be
`
`accomplished; to avoid economic upheaval, the transition must be accomplished in an
`
`economically feasible fashion.
`
`Furan derivatives (such as furfural (Fur) and 5-hydroxymethylfurfural (HMF))
`
`derived from renewable biomass resources have potential as substitutes for petroleum-
`
`based building blocks used to produce plastics and fine chemicals. For example, HMF
`
`can be converted to 2,5-furandicarboxylic acid (FDCA) by selective oxidation; FDCA
`
`can be used as a replacement for terephthalic acid in the production of polyesters such as
`
`polyethyleneterephthalate (PET) and polybutyleneterephthalate (PBT). Reducing HMF
`
`leads to products such as 2,5-dihydroxymethylfuran and 2,5-
`
`bis(hydroxymethyDtetrahydrofuran, which can function as the alcohol components in the
`
`production of polyesters (thereby leading to completely biomass-derived polymers when
`
`combined with FDCA). Additionally, disubstituted furan derivates obtained from HMF
`
`serve as an important component of pharmacologically active compounds associated with
`
`a wide spectrum of biological activities. Furfural is also a key chemical for the
`
`commercial production of furan (via catalytic decarbonylation) and tetrahydrofuran (via
`
`hydrogenation), thereby providing a biomass-based alternative to the corresponding
`
`petrochemical production route (via dehydration of 1,4-butanediol).
`
`Furfural is primarily used in refining lubricating oil. Furfural is also used in
`
`condensation reactions with formaldehyde, phenol, acetone or urea to yield resins with
`
`excellent thermosetting properties and extreme physical strength. Methyl-
`
`tetrahydrofuran (MeTHF), a hydrogenated form of furfural, is a principal component in
`
`P-series fuel, which is developed primarily from renewable resources. (“P-series fuel” is
`
`an official designation promulgated by the U.S. Dept. of Energy for a fuel blend
`
`comprised of pentanes, ethanol, and biomass-derived MeTHF. See 10 CFR §490.)
`
`However, as indicated by various authors, the industrial use of HMF as a
`
`chemical intermediate is currently impeded by high production costs. Perhaps because of
`
`the high cost of production, a number of U.S. and foreign patents describe methods to
`
`produce HMF. See, for example, U.S. Patent Nos. 2,750,394 (to Peniston); 2,917,520 (to
`
`Cope); 2,929,823 (to Garber); 3,118,912 (to Smith); 4,339,387 (to Fleche et al.);
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`Petitioners‘ Exhibit 1016, Page 4 of 66
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`4,590,283 (to Gaset et al.); and 4,740,605 (to Rapp). In the foreign patent literature, see
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`GB 591,858; GB 600,871; and GB 876,463, all of which were published in English. See
`
`also FR 2,663,933; FR 2,664,273; FR 2,669,635; and CA 2,097,812, all of which were
`
`published in French.
`
`Producing furfural from biomass requires raw materials rich in pentosan, such as
`
`comcobs, oat hulls, bagasse, and certain woods (like beech). Even today, most furfural
`
`production plants employ batch processing using the original, acid-catalyzed Quaker Oats
`
`technology (first implemented in 1921 by Quaker Oats in Cedar Rapids, Iowa as a means
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`to realize Value from the tons of oat hulls remaining after making rolled oats). (For an
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`exhaustive history on the production of furfural, see K.J. Zeitsch, “The Chemistry and
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`Technology of Furfural and its Many By-Products,” Elsevier, Sugar Series, No. 13, ©
`
`2000, Elsevier Science B.V.) This batch processing results in yields less than 50%, and
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`also requires a large amount of high-pressure steam. The process also generates a
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`significant amount of effluent.
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`Various researchers have tried dehydration of xylose into furfural using acid
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`catalysts such as mineral acids, zeolites, acid—functionalized Mobile crystalline materials
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`(MCM’s) and heteropolyacids. Moreau et. al. has conducted the reaction in a batch mode
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`using H-form fauj asites and a H-mordenite catalyst, at 170°C, in a solvent mixture of
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`water and methylisobutylketone (MIBK) or toluene (1 :3 by Vol) with selectivities ranging
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`from 70-96% (in toluene) and 50-60% (in MIBK) but at low conversions. Dias et al.
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`showed that a sulfonic acid-modified MCM-41-type catalyst displayed fairly high
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`selectivity to furfural (~82%) at high xylose conversion (>90%) with toluene as the
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`extracting solvent for the reactions carried out 140°C. In the patent literature, see, for
`
`example, U.S. Patent Nos. 4,533,743 (to Medeiros et al.); 4,912,237 (to Zeitsch);
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`4,971,657 (to Avignon et al.); and 6,743,928 (to Zeitsch).
`
`Abundant biomass resources are a promising sustainable supply of valuable
`
`intermediates (e. g. , alcohols, aldehydes, ketones, carboxylic acids) to the chemical
`
`industry for producing drugs and polymeric materials. In this context, the high content of
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`oxygenated functional groups in carbohydrates, the dominant compounds in biomass, is
`
`an advantage. (Which is in contrast to the drawbacks of such functionality for the
`
`conversion of carbohydrates to fuels.) However, there remains a long—felt and unmet
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`Petitioners‘ Exhibit 1016, Page 5 of 66
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`need for efficient processes to selectively remove excess functional groups and to modify
`
`other functional groups to create commercially desirable products from biomass.
`
`SUMMARY OF THE INVENTION
`
`The present invention is a method for the selective dehydration of carbohydrates
`
`(preferably fructose) to produce furan derivatives (preferably 5-hydroxymethylfurfural
`
`(HMF). The method is highly useful because it provides a cost-effective route for
`
`making these valuable chemical intermediates. Indeed, HMF and its ensuing 2,5-
`
`disubstituted furan derivatives could replace key petroleum-based building blocks (1).
`
`For example, HMF can be converted to 2,5-furandicarboxylic acid (FDCA) by selective
`
`oxidation, and Werpy and Petersen (2) and Pentz (3) have suggested that FDCA can be
`
`used as a replacement for terephthalic acid in the production of polyesters such as
`
`polyethyleneterephthalate (PET) (2) and polybutyleneterephthalate (PBT). They have
`
`also suggested that the reduction of HMF can lead to products such as 2,5-
`
`dihydroxymethylfuran and 2,5-bis(hydroxymethyl)tetrahydrofuran, which can serve as
`
`alcohol components in the production of polyesters, thereby leading to completely
`
`biomass-derived polymers when combined with FDCA. In addition, HMF can serve as a
`
`precursor in the synthesis of liquid alkanes to be used, for example, in diesel fuel (4).
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`Unfortunately, as noted by various authors (5-8), the industrial use of HMF as a
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`chemical intermediate is currently impeded by high production costs. Early work showed
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`that HMF could be produced in high concentrations using high-boiling organic solvents,
`
`such as dimethylsulfoxide (DMSO), dimethylformamide, and mixtures of
`
`polyethyleneglycol (PEG) with water, over various catalysts including sulfuric acid and
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`sulfonic acid resins; however, this approach necessitates difficult and energy intensive
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`isolation procedures (6, 9-13). In pure water, fructose dehydration is generally non-
`
`selective, leading to many byproducts besides HMF (I 4). Recent advances have shown
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`improved results in pure water or in water-miscible solvent systems (e.g., acetonitrile or
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`acetone), but only using low initial fructose concentrations which inevitably generate low
`
`HMF concentrations (1, 10, 15, I 6). Biphasic systems, where a water-immiscible organic
`
`solvent is added to extract continuously the HMF from the aqueous phase, have also been
`
`investigated using mineral acid or zeolite catalysts at temperatures above 450 K (6, I 7-
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`Petitioners‘ Exhibit 1016, Page 6 of 66
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`21). However, poor HMF partitioning into the organic streams employed in these studies
`
`necessitated large amounts of solvent, thereby requiring large energy expenditures to
`
`purify the diluted HMF product (22).
`
`Thus, the present invention is directed to a process to make furan derivative
`
`compounds. The process comprises dehydrating a carbohydrate feedstock solution,
`
`optionally in the presence of an acid catalyst, in a reaction vessel containing a biphasic
`
`reaction medium comprising an aqueous reaction solution and a substantially immiscible
`
`organic extraction solution. The aqueous reaction solution, the organic extraction
`
`solution, or both the aqueous reaction solution and the organic extraction solution,
`
`contain at least one modifier to improve selectivity of the process to yield furan
`
`derivative compounds in general, and HMF in particular.
`
`In the preferred embodiment, the process includes an aqueous reaction solution
`
`containing the carbohydrate, an acid catalyst, and a chemical modifier. The modifier is
`
`comprised of an inorganic salt and/or a dipolar, aprotic additive. The acid catalyst
`
`preferably is selected from the group consisting of mineral acids. The aqueous phase
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`modifier preferably comprises an inorganic salt selected from the group consisting of
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`metal halides, sulfates, sulfides, phosphates, nitrates, acetates, and carbonates; and the
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`dipolar, aprotic additive is selected from the group of additives such as dimethylsulfoxide
`
`(DMSO), dimethylforrnamide, N-methylpyrrolidinone (NMP), acetonitrile,
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`butyrolactone, dioxane, pyrrolidinone; water—miscible alcohols or ketones (methanol,
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`ethanol, acetone); and water-soluble polymers such as polyethylene glycol (PEG) and
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`poly(l-Vinyl-2-pyrrolidinone) (PVP).
`
`In the preferred versions of the invention, the organic extraction solution
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`comprises an alcohol (1-butanol is preferred), a ketone (MIBK is preferred), and/or a
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`chlorinated alkane (DCM is preferred) which is immiscible with the chemically modified
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`aqueous phase. Where DCM is used, it is also preferred that the reaction be carried out
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`without an acid catalyst. The organic extraction solution is preferably modified with a C1-
`
`to C12-alcohol, more preferably a primary or secondary, linear, branched, or cyclic C3- to
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`Cg-alkanol, and most preferably 2-butanol. The organic extraction solution and the
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`aqueous reaction solution preferably are present in a volume ratio of from about 0.121 to
`
`about 100:1 (organic extraction s01ution:aqueous reaction solution). As a general rule,
`
`Petitioners‘ Exhibit 1016, Page 7 of 66
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`Petitioners' Exhibit 1016, Page 7 of 66
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`the dehydration reaction is carried out at a temperature ranging from about 70°C to about
`
`250°C. Higher temperatures may be used where the acid catalyst is heterogeneous, such
`
`as a zeolite catalyst.
`
`The dehydration reaction is preferably carried out at pressures ranging from about
`
`1 bar to about 200 bars, using carbohydrate feedstock solutions comprising 1 — 70 wt%
`
`carbohydrate (about 10 to 50 wt% is preferred).
`
`The invention is more particularly directed to a method of making a compound of
`
`Formula 1::
`
`W (D
`
`wherein each R is independently selected from the group consisting of hydrogen,
`
`C1-C6-alkyl, hydroxy-C1-C6-alkyl, acyl-C1-C6-alkyl, C1-C5-alkylcarbonyl-C1-C5-alkyl,
`
`and carboxy—C1-C6-alkyl, and provided the both R’s are not simultaneously hydrogen.
`
`The method comprises dehydrating a feedstock solution comprising a carbohydrate, in
`
`the presence of an acid catalyst, in a reaction vessel containing a biphasic reaction
`
`medium. The biphasic reaction medium preferably comprises (i) an aqueous reaction
`
`solution comprising water and one or more modifiers (e.g., NaCl or DMSO); and (ii) an
`
`organic extraction solution that is immiscible with the aqueous reaction solution.
`
`Preferably, the organic extraction solution comprises, by way of non—limiting examples,
`
`l-butanol, DCM or a mixture of MIBK and 2-butanol.
`
`In the preferred versions of the process, the organic extraction solution comprises
`
`a solvent selected from the group consisting of unsubstituted aliphatic and aromatic
`
`hydrocarbons and halo-substituted aliphatic and aromatic hydrocarbons. Water-
`
`immiscible, linear, branched, or cyclic alcohols, ethers, and ketones may also be used as
`
`the organic extraction solution. Any combination of these solvents may also be used.
`
`In one particularly preferred version of the invention, the aqueous reaction
`
`solution further comprises at least one salt, thereby yielding a saline aqueous reaction
`
`solution. Any salt that is non-reactive with the dehydration reaction taking place can be
`
`used. The salts comprise a cation and an anion. A non—limiting list of suitable anions
`
`that can be used in the salt in include acetate, alkylphosphate, alkylsulfate, carbonate,
`
`chromate, citrate, cyanide, forrnate, glycolate, halide, hexafluorophosphate, nitrate,
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`Petitioners‘ Exhibit 1016, Page 8 of 66
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`Petitioners' Exhibit 1016, Page 8 of 66
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`nitrite, oxide, phosphate, sulfate, tetrafluoroborate, tosylate, triflate, and bis-
`
`trifluorsulfonimide. A non-limiting list of suitable cations includes Group I and II
`
`metals, the most preferred of these being Na, K, Mg, and Ca. NaCl is the preferred salt.
`
`Two or more different salts my also be used. The salt can be added in small amount or
`
`added until the aqueous reaction solution is saturated in the chosen salt. When the
`
`aqueous solution contains salt, the organic extraction solution comprises a solvent that is
`
`substantially immiscible in the saline aqueous reaction solution. Note that many organic
`
`solvents, such as acetone, are miscible in water, but are immiscible, for example, in a
`
`saturated aqueous solution of NaCl.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1A is a schematic diagram depicting reaction pathways for the acid-
`
`catalyzed dehydration of polysaccharides containing hexose monomer units. The
`
`structures in brackets correspond to representative species.
`
`FIG. 1B is a graph depicting the rationale for converting carbohydrates to 2,5-
`
`dimethylfuran (DMF). Oxygen content is depicted on the X-axis and boiling point on the
`
`Y-axis for each compound shown.
`
`FIG. 2 is a graph depicting the effect of salt content (NaCl) in the aqueous phase
`
`on the extraction ratio R and HMF selectivity when practicing present invention using as
`
`a feedstock 30 wt% fructose and using 2-butanol as the extracting solvent.
`
`FIG. 3 is a graph depicting the effect of extraction ratio R on HMF selectivity
`
`from 30 wt% fructose feeds for various organic solvents. Open symbols correspond to
`
`experiments without NaCl and closed symbols correspond to experiments with an
`
`aqueous phase saturated with NaCl. Solvent legend: 2-butanol (0, 0) (closed diamonds
`
`refer to experiments using 2-butanol as the extracting solvent and aqueous phases
`
`containing 5, 15, 25, and 35% NaCl; the open diamond refers to an experiment using 2-
`
`butanol with no salt and a VO[gNaq = 1.6), 1-butanol (A, A), 1-hexanol (V, V), MIBK
`
`(O, 0), 5:5 toluene:2-butanol (F, [>), No solvent (I,Ei).
`
`FIGS. 4A, 4B, and 4C are graphs depicting the effects of changing the aqueous
`
`phase composition from water (“W”), to 8:2 water:DMSO (w/w) (“W:D”), to 7:3
`
`water:PVP (w/w) (“W:P”), to 7:3 (8:2 water:DMSO):PVP (w/w) (W:D:P). FIG. 4A
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`Petitioners‘ Exhibit 1016, Page 9 of 66
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`depicts HMF selectivity (%) using a 30 wt% fructose feed. The white bars represent
`
`MIBK as the extracting solvent; the grey bars represent 7:3 (w/w) MIBK:2—butano1 as the
`
`extracting solvent. FIG. 4B depicts the extraction ratio, R, using MIBK (white bars) or
`
`7:3 (w/w) MIBK:2—butano1 (grey bars) as the extracting solvent. Fig. 4C depicts HMF
`
`selectivity (%) using 7:3 (W/W) MIBK:2—butano1 extracting solvent: white bars depict
`
`using a 30 wt% fructose feed; grey bars depict using a 50 wt% fructose feed; hatched bars
`
`depict the improvement obtained using double the amount of extracting solvent.
`
`FIG. 5 is a schematic diagram depicting a reactor for producing HMF from
`
`fructose, including simulated countercurrent extraction and evaporation apparatus. The
`
`aqueous phase (white) containing fructose, the acid catalyst, and the aqueous phase
`
`chemical modifiers is represented in the bottom half of the reactor R1. The organic phase
`
`(grey) containing the extracting solvent (e.g. 1-butanol or MIBK:2—butano1) is
`
`represented in the top half of the reactor R1.
`
`FIG. 6 is a graph depicting the effect of adding aqueous modifiers to the aqueous
`
`phase (4:6 water:DMSO) (W/w) and the extracting organic phase (7:3 MIBK:2—butano1)
`
`(W/W) on the selectivity and conversion rates for 10 wt% glucose dehydration. White
`
`bars represent conversion; grey bars represent selectivity.
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`FIG. 7 is a graph depicting the effect of acid concentration on the selectivity (%)
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`for dehydration of 10 wt% solutions of simple sugars fructose, glucose, and xylose.
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`These experiments were conducted in a 5:5 water:DMSO mixture at 443 K using 7:3
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`MIBK:2—butano1 as the extracting solvent. White bars = pH 1.0; light grey bars = pH 1.5;
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`dark grey bars = pH 2.0.
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`FIG. 8 is a graph depicting the effects of varying the DMSO concentration on 10
`
`wt% glucose dehydration at a constant pH of 1.0, at 443 K, using 7:3 MIBK:2—butano1 as
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`the extracting solvent.
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`FIG. 9 is a graph depicting the effect on selectivity of subjecting a variety of
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`carbohydrate precursor molecules with 10 wt% initial concentrations at optimized
`
`conditions for their monomer units. White bars present a water:DMSO aqueous reaction
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`mix using HCl as the catalyst; grey bars represent using 3:7 water:DMSO — 5 DCM.
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`FIG. 10 is a graph depicting the effect of using different mineral acids as the
`
`catalyst on 10 wt% glucose dehydration. Along with HCI, experiments were conducted
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`Petitioners‘ Exhibit 1016, Page 10 of 66
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`Petitioners' Exhibit 1016, Page 10 of 66
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`WO 2007/146636
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`PCT/US2007/070313
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`with H2SO4 and H3PO4 at pH 1.5 and 5:5 water:DMSO (w/w) as the aqueous phase and
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`7:3 MIBK:2—butanol (w/w) as the extracting solvent.
`
`DETAILED DESCRIPTION
`
`Abbreviations and Definitions: The following abbreviations and definitions are
`
`used throughout the specification and claims. Words and phrases not explicitly defined
`
`herein are to be afforded their standard definition in the art of chemical engineering.
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`1B = NaCl
`
`2B = 2—butanol.
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`Biomass = any plant material, vegetation, or agricultural waste, from any source,
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`that can be used to supply carbohydrates to be used as reactants in the process disclosed
`
`herein.
`
`Carbohydrates = Any of a group of organic compounds that includes (without
`
`limitation) sugars, starches, celluloses, and gums and serves as a major energy source in
`
`the diet of animals. Carbohydrates are produced by photosynthetic plants and contain
`
`only carbon, hydrogen, and oxygen atoms.
`
`DCM = dichloromethane.
`
`Dipolar, aprotic additive = a water—soluble compound that: (a) cannot donate
`
`labile hydrogen atoms to form strong hydrogen bonds; (b) has a dielectric constant
`
`greater than about 15; and (c) has a permanent dipole moment. dimethylformamide,
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`DMSO, NMP, pyrrolidinone, and PVP are examples of dipolar, aprotic additives.
`
`DMF = dimethylfuran.
`
`DMSO = dimethylsulfoxide.
`
`FDCA = 2,5-furandicarboxylic acid.
`
`Fur = furfural.
`
`Furan derivative compounds: A compound having the structure:
`
`R
`
`0
`
`R
`
`U
`
`wherein each R is independently selected from the group consisting of hydrogen,
`
`C1-C5-alkyl, hydroxy—C1—C6-alkyl, acyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl,
`
`30
`
`and carboxy-C1-C5-alkyl, and provided the both R’s are not simultaneously hydrogen.
`
`10
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`Petitioners‘ Exhibit 1016, Page 11 of 66
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`Petitioners' Exhibit 1016, Page 11 of 66
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`(Furan itself is the compound where both R groups are hydrogen.) Explicitly included
`
`within the phrase “furan derivative” are 5—hydroxymethylfurfural and furfural.
`
`Group VHIB metal: a metal selected from the group consisting of Fe, Co, Ni, Ru,
`
`Rh, Pd, Os, lr, and Pt.
`
`HMF = 5-hydroxymethylfurfural.
`
`MeTHF = methyltetrahydrofuran.
`
`MIBK = methylisobutylketone.
`
`MCM = mobile crystalline materials.
`
`NaC1 = sodium chloride
`
`NMP = l-methyl-2-pyrrolidinone.
`
`PBT = polybutyleneterephthalate.
`
`PEG = polyethyleneglycol
`
`PET = polyethyleneterephthalate.
`
`PVP = poly(1-vinyl-2-pyrrolidinone).
`
`Overview: In the present invention, a carbohydrate, preferably a simple sugar
`
`such as glucose, fructose, xylose, and the like, or more complex carbohydrates such as
`
`starch, cellobiose, sucrose, inulin, xylan, and the like, is dehydrated, optionally in the
`
`presence of an acid catalyst, to produce furan derivatives, such as HMF and various
`
`byproducts, as shown in Fig. 1A. Fig. 1A depicts various possible products for a reaction
`
`according to the present invention, using polysaccharides with hexose monomer units as
`
`the carbohydrate reactant. Although evidence exists supporting both the open-chain and
`
`the cyclic fructofuransyl intermediate pathways shown between brackets in Fig. 1A (20,
`
`23), it is clear that the reaction intermediates and the furan derivative products degrade
`
`via processes such as fragmentation, condensation, rehydration, reversion, and/or
`
`additional dehydration reactions, as shown in Fig. 1A. (Note that Fig. 1A depicts
`
`representative reactants, products, and by-products, and is by no means limiting or
`
`exhaustive.)
`
`The rationale for converting carbohydrates to 2,5—dimethylfuran (DMF) is
`
`outlined in Fig. 1B. The selective removal of five oxygen atoms from a hexose (e.g.,
`
`fructose, 2) to produce DMF not only decreases the boiling point to a value suitable for
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`Petitioners‘ Exhibit 1016, Page 12 of 66
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`Petitioners' Exhibit 1016, Page 12 of 66
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`WO 2007/146636
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`liquid fuels, but also attains the lowest water solubility and the highest research octane
`
`number of the mono-oxygenated C5 compounds (30), while preserving a high energy
`
`density (30 kJ/cm3). This selective removal of oxygen atoms can be accomplished in two
`
`steps: (1) removing three oxygen atoms by dehydration to produce 5-
`
`hydroxymethylfurfural (HMF); and (2) removing two oxygen atoms by hydrogenolysb to
`
`produce DMF via intermediates 4 and 5 as shown in Fig. 1B. Species 6, produced via 7,
`
`is a hydrogenolysis byproduct that also possesses excellent fiael qualities.
`
`The present invention is a method of making furan derivative compounds. The
`
`method addresses the key furan derivative production limitations using a modified
`
`biphasic reaction system. In short, the method of the present invention maximizes
`
`production of the desired furan derivative compounds, using any type of carbohydrate
`
`(but most preferably simple sugars) as the reactant. Specifically, the present invention is
`
`a process that vastly improves the selectivity for furan derivatives such as HMF (defined
`
`as the moles of HMF produced divided by the moles of carbohydrate reacted) of an acid-
`
`catalyzed dehydration of concentrated (10-50 wt%) carbohydrate feeds by adding
`
`modifiers to one or both phases in a biphasic reaction solution (an aqueous reaction phase
`
`and a non-aqueous extraction phase). When using specific two-phase systems, most
`
`notably when the organic phase is dichloromethane and the aqueous reaction phase is a
`
`mixture of water and DMSO, the acid catalyst can be omitted entirely. In this particular
`
`biphasic system, fiiran derivative compounds can be produced at high selectivities and
`
`conversion rates without adding an acid catalyst.
`
`In the preferred embodiment, the reactive aqueous phase containing the acid
`
`catalyst and the carbohydrate reactant (preferably a sugar) is optionally modified with
`
`one or more modifiers consisting of metal salts (preferably NaC1) and/or dipolar, aprotic
`
`additives (preferably DMSO and/or l-methyl-2-pyrrolidinone (NMP)) and/or a
`
`hydrophilic polymer (preferably poly(l-vinyl-2-pyrrolidinone) (PVP)). The aqueous-
`
`phase-immiscible organic phase (preferably 1-butanol or MIBK) used during the reaction
`
`(to extract the furan derivative product) is preferably modified with a C1- to C12-alcohol,
`
`more preferably a primary or secondary, linear, branched, or cyclic C3- to Cg-alkanol, and
`
`most preferably 2-butanol. The ratio of relative volumes of the organic and aqueous
`
`phases in the reactor (Vorg/Vaq)9 as Well as the ratio of the product concentration in the
`
`Petitioners‘ Exhibit 1016, Page 13 of 66
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`Petitioners' Exhibit 1016, Page 13 of 66
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`organic layer to that in the aqueous layer (defined as the extraction ratio, R) proved to be
`
`important variables in the process (as described below). Upon completion of the
`
`dehydration reaction, both pha