(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0156841 A1
`SANBORN et al.
`(43) Pub. Date:
`Jun. 18, 2009
`
`US 20090156841A1
`
`(54) CONVERSION OF CARBOHYDRATES TO
`HYDROXYME THYLFURFURAL (HMF) AND
`DERIVATIVES
`
`(76) Inventors:
`
`Alexandra J. SANBORN, Lincoln,
`IL (Us); Stephen J- Howard,
`Sherman’ IL (Us)
`
`Correspondence Address;
`MCDERMOTT WILL & EMERY LLP
`600 13TH STREET, N_W_
`WASHINGTON DC 20005_3096 (Us)
`’
`
`(21) APP1~ N05
`
`12/334’038
`
`(22) Filed;
`
`Dec, 12, 2008
`
`.
`.
`Related U's' Apphcatlon Data
`(60) Provisional application No, 61/006,012, ?led on Dee~
`14, 2007, provisional application No. 60/996,946,
`?led on Dec. 12, 2007.
`
`Publication Classi?cation
`
`(51) Int‘ Cl‘
`(2006.01)
`C07D 307/50
`(2006.01)
`C07C 51/00
`(2006.01)
`C07C 69/704
`(52) us. Cl. ........................ .. 549/488; 562/515; 560/180
`(57)
`ABSTRACT
`
`A method of producing substantially pure HMF, HMF esters
`and other derivatives from a carbohydrate source by contact
`ing the carbohydrate source With a solid phase catalyst. A
`carbohydrate starting material is heated in a solvent in a
`column and continuously ?oWed through a solid phase cata
`lyst in the presence of an organic acid, or heated With the
`organic acid and a solid catalyst in solution to form a HMF
`ester. Heating Without organic acid forms HMF. The resulting
`product is puri?ed by ?ltration to remove the unreacted start
`ing materials and catalyst. The HMF ester or a mixture of
`HMF and HMF ester may then be oxidized to 2,5-furandicar
`boxylic acid (FDCA) by combining the HMP ester With an
`organic acid, cobalt acetate, manganese acetate and sodium
`bromide under pressure. Alternatively, the HMP ester may be
`reduced to form a furan or tetrahydrofuran diol.
`
`Petitioners' Exhibit 1022, Page 1 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 1 0f 11
`
`US 2009/0156841 A1
`
`FIG. 1
`PRIOR ART
`
`Petitioners' Exhibit 1022, Page 2 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 2 0f 11
`
`US 2009/0156841 A1
`
`AUTOOLAVE REACTIONS
`
`0.25
`
`
`
`FRACTION OF AcHMF CONVERSION
`
`110C,
`WITH
`RESIN
`
`125C,
`NO
`RESIN
`
`1250,
`WITH
`RESIN
`
`150C,
`WITH
`RESIN
`
`150C,
`NO
`RESIN
`
`FIG. 2
`PRIOR ART
`
`Petitioners' Exhibit 1022, Page 3 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 3 0f 11
`
`US 2009/0156841 A1
`
`ACETIC ACID COLUMN RESULTS
`
`0.45
`
`035*
`C) (A) l
`0.25—
`
`015*
`
`
`
`FRACTION OF AcHII/IF CONVERSION
`
`PULSE TEST:
`AMBERLYST
`35 RESIN
`
`GRAVITY
`GRAVITY
`COLUMN:
`COLUMN‘.
`AMBERLYST AMBERYLST
`35 RESIN
`35 RESIN
`FIG. 3
`
`Petitioners' Exhibit 1022, Page 4 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 4 0f 11
`
`US 2009/0156841 A1
`
`4887.29: ACETIC ACID RESIN TEST, 80.0 DEG c
`1.48 mL/MIN (1-33), 1.36 mL/MIN (37-63)
`
`+AcHMF
`22?: -
`
`@ 0-06- +FRUCTOSE
`5 0.05
`g 0.04
`6 0.03
`E 0.02
`0.01~
`lo
`-0.01
`
`A c:
`
`M 0
`
`50
`
`60
`
`70
`
`‘I: ‘
`
`='T-_
`
`40
`30
`WE (MtN)
`FIG. 4
`
`Petitioners' Exhibit 1022, Page 5 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 5 0f 11
`
`US 2009/0156841 A1
`
`43,177,810
`
`CHROMATOGRAM (ZOOM)
`
`HMF/121852741
`
`AcHMF/30040100
`
`TIME-(MIN)
`FIG. 5
`
`Petitioners' Exhibit 1022, Page 6 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 6 0f 11
`
`US 2009/0156841 A1
`
`PTS1d14096 |
`
`
`
`LB: 0.0
`
`4
`
`
`
`OF1: 5400 NA: 1 FIG. 6
`
`
`
`PW: 21.9 us PD: 1.0 sec
`
`
`
`SW1: 1501
`
`
`
`1'0 ' ' '
`
`
`
`F1:90.019 I Fx 0 \eft\globa1\zgh ppg
`
`Petitioners' Exhibit 1022, Page 7 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 7 0f 11
`
`US 2009/0156841 A1
`
`
`
`lll'lllllll|llllllllllI'lllllllllllllllllllllllllllllllllIIIIIIIIIII‘IFIIIIlllllllllllllllllII lllllllll‘
`
`0. PPM
`
`1.0
`
`2.0
`
`3.0
`
`
`
`5.0 4.0
`
`FIG. 7
`
`6.0
`
`7.0
`
`8.0
`
`9.0
`
`Petitioners' Exhibit 1022, Page 8 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 8 0f 11
`
`US 2009/0156841 A1
`
`7.31
`
`2.00
`
`0.70
`
`0.05
`
`0.01
`
`'10"'é"'6' '4"'é"'PPM
`
`FIG. 8
`
`Petitioners' Exhibit 1022, Page 9 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 9 0f 11
`
`US 2009/0156841 A1
`
`
`
`1.5m? us; “512
`
`SPD-10AV Ch1-280nm
`111406 jlm HFCS sys5 AS 05595 4816-264d
`
`NAME
`RETENTION TIME
`
`
`
`was $2 @EN EN
`
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`
`
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`
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`
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`
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`
`$2 a: N,
`5 gm . é as H.
`
`as 52 H.
`
`Q
`
`MINUTES
`FlG. 9
`
`Petitioners' Exhibit 1022, Page 10 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 10 0f 11
`
`US 2009/0156841 A1
`
`9110/00
`
`0000 10m
`
`——--6VZ9€6HWH°VL66'LL:_
`0000a 00m
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`5% <23
`m: EM:
`55$
`
`osz<
`
`Petitioners' Exhibit 1022, Page 11 of 23
`
`

`
`Patent Application Publication
`
`Jun. 18, 2009 Sheet 11 0f 11
`
`US 2009/0156841 A1
`
`100:
`——SPD-1OA\/Ch1-280nm
`i
`11150011111 HFCS sys5AS 05024 4010-20-4
`140:
`120% NAME
`1 RETENTIONTIME
`100-; AREA
`E80";
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`
`Petitioners' Exhibit 1022, Page 12 of 23
`
`

`
`US 2009/0156841A1
`
`Jun. 18, 2009
`
`CONVERSION OF CARBOHYDRATES TO
`HYDROXYME THYLFURFURAL (HMF) AND
`DERIVATIVES
`
`CROSS REFERENCE TO PROVISIONAL
`APPLICATION
`
`[0001] This application is based upon and claims the ben
`e?t of priority from Provisional US. Patent Application
`61/006,012 (Attorney Docket No. 010253-0020) ?led on
`Dec. 14, 2007, and from Provisional US. Patent Application
`60/996,946 (Attorney Docket No. 010253-0021) ?led on
`Dec. 12, 2007, the entire contents of Which are incorporated
`by reference herein.
`
`TECHNICAL FIELD
`
`[0002] The present invention relates to a process for the
`synthesis and recovery of substantially pure HMF and deriva
`tives thereof from hexose carbohydrate feedstocks such as
`fructose or high fructose corn syrup (HFCS). More particu
`larly, HMF and its derivatives are synthesiZed, separated, and
`recovered via contact of the carbohydrate With strong acid
`cation exchange resins, such as a solid phase catalyst.
`
`BACKGROUND
`
`[0003] A major product in the acid-catalyZed dehydration
`of fructose is 2-hydroxymethyl-5-furfuraldehyde, also
`knoWn as hydroxymethyl?lrfural (HMF). The structure of
`HMF is shoWn below:
`
`0
`
`Hydroxymethylfurfural
`[0004]
`[0005] HMF represents one key intermediate substance
`readily accessible from reneWable resources like carbohy
`drates and is a suitable starting source for the formation of
`various furan monomers Which are used for the preparation of
`non-petroleum-derived polymeric materials. While not being
`bound by theory, it is generally believed that fructose is con
`verted to HMF via an acyclic pathWay, although evidence also
`exists for the conversion to HMF via cyclic fructofuransyl
`intermediate pathWays. Regardless of the mechanism of
`HMF formation, the intermediate species formed during the
`reaction may in turn undergo further reactions such as con
`densation, rehydration, reversion and other rearrangements,
`
`resulting in a plethora of unWanted side products. BeloW is
`one proposed pathWay for the conversion of fructose to HMF:
`
`CH0
`
`CH0
`
`H —— OH
`
`— OH
`
`HO——H -H2O
`
`—H -H2O
`
`H —— OH
`
`H —— OH
`
`H —— OH
`
`H —— OH
`
`LHZOH
`
`LHZOH
`
`HO
`
`0
`
`\ /
`
`O
`
`H
`
`H
`
`H
`
`OH
`
`CHZOH
`
`-H2%
`
`O
`
`H
`
`[0006] HMF and 2,5-disubstituted furanic derivatives have
`great potential in the ?eld of intermediate chemicals from
`regroWing resources. Due to its various functionalities, it has
`been proposed that HMF could be utiliZed to produce a Wide
`range of products such as polymers, solvents, surfactants,
`pharmaceuticals, and plant protection agents, and has been
`reported to have antibacterial and anticorrosive properties.
`HMF is also a key component, as either a starting material or
`intermediate, in the synthesis of a Wide variety of compounds,
`such as furfuryl dialcohols, dialdehydes, esters, ethers,
`halides and carboxylic acids.
`[0007] In addition, HMF has great potential as a biofuel,
`Which are fuels derived from biomass and are considered
`promising alternatives to fossil fuels. HMF is also currently
`under investigation as a treatment for sickle cell anemia. In
`short, HMF is an important chemical compound and a method
`of synthesis on a large scale to produce HMF absent signi?
`cant amounts of impurities, side products and remaining start
`ing material has been sought for nearly a century.
`[0008] HMF is a suitable starting source for the formation
`of various furan monomers used in the preparation of non
`petroleum-derived polymeric materials. A furan is a 5-mem
`bered heterocyclic organic compound. HMF and 2,5-disub
`stituted furanic derivatives have great potential in the ?eld of
`intermediate chemicals from groWing resources. Due to its
`various functionalities, it has been proposed that HMF may
`be utiliZed to produce a Wide range of products such as poly
`mers, solvents, surfactants, pharmaceuticals, and plant pro
`tection agents, and HMF has been reported to have antibac
`terial and anticorrosive properties.
`[0009] Although preparation of HMF has been knoWn for
`many years, a method Which provides HMF With good selec
`tivity and in high yields has yet to be found. Complications
`arise from the rehydration of HMF, Which yields by-products,
`such as, levulinic and formic acids. Another unWanted side
`
`Petitioners' Exhibit 1022, Page 13 of 23
`
`

`
`US 2009/0156841A1
`
`Jun. 18, 2009
`
`reaction includes the polymerization of HMF and/or fructose
`resulting in humin polymers, Which are solid Waste products.
`Further complications may arise as a result of solvent selec
`tion. Water is easy to dispose of and dissolves fructose, but
`unfortunately, loW selectivity and increased formation of
`polymers and humin increases under aqueous conditions.
`[0010] Agricultural raW materials such as starch, cellulose,
`sucrose or inulin are inexpensive starting materials for the
`manufacture of hexoses, such as glucose and fructose. As
`shoWn above, these hexoses can in turn, be converted to HMF.
`The dehydration of sugars to produce HMF is Well knoWn.
`HMF Was initially prepared in 1895 from levulose by Dull
`(Chem. Zlg, 19, 216) and from sucrose by Kiermayer (Chem.
`Zlg, 19, 1003). HoWever, these initial syntheses Were not
`practical methods for producing HMF due to loW conversion
`of the starting material to product.
`[0011] Commonly used catalysts for the preparation of
`HMF includes cheap inorganic acids such as H2SO4, H3PO4,
`and HCl. These acid catalysts are used in solution and are
`dif?cult to regenerate. In order to avoid the regeneration and
`disposal problems, solid sulfonic acid catalysts have been
`used. Unfortunately, the usefulness of solid acid resins is
`limited because of the formation of deactivating humin poly
`mers on the surface of the resins.
`[0012] The puri?cation of HMF has also proved to be a
`troublesome operation. On long exposure to temperatures at
`Which the desired product can be distilled, HMF and impuri
`ties associated With the synthetic mixture tend to form tarry
`degradation products. Because of this heat instability, a fall
`ing ?lm vacuum still must be used. Even in such an apparatus,
`resinous solids form on the heating surface causing a stalling
`in the rotor and frequent shut doWn time making the operation
`inef?cient. Prior Work has been performed With distillation
`and the addition of a non-volatile solvent like PEG-600 to
`prevent the buildup of solid humin polymers (Cope, US. Pat.
`No. 2,917,520). Unfortunately, the use of polyglycols leads to
`the formation of HMF-PEG ethers.
`[0013] The prior art processes also fail to provide a method
`for producing HMF that can be performed economically. For
`example, Besemer et al Netherlands Organ. Appl. Sci. Res.
`Nulr. Food Res., describes the enZymatic synthesis of HMF
`esters. This process requires the use of expensive enzymes
`and therefore does not provide an economically feasible route
`to synthesiZing HMF esters.
`[0014] Garber et al., Canadian Patent 6 54240, describe the
`synthesis of the 2,5-tetrahydrofurandimethanol monoesters
`from HMF using excess amounts of anhydride and pyridine
`solvent. Reduction is performed using Raney Ni catalyst in
`diethyl ether. HoWever the reference does not disclose the
`synthesis of HMF esters from fructose or using a carboxylic
`acid. Furthermore, the removal of Raney Ni catalyst is dan
`gerous and the costs of disposing the catalyst may be burden
`some.
`[0015] The present disclosure, Which is directed, in-part, to
`chromatographic processes for the synthesis and recovery of
`HMF from natural resources addresses and eliminates these
`problems and provides high purity products. In addition to
`HMF, studies have broadened to include the synthesis and
`puri?cation of a variety of HMF derivatives. Derivatives of
`particular interest include the esters of HMF, and oxidiZed
`forms (2,5-diformylfuran, 2,5-furandicarboxylic acid and
`acid ester), and the reduced forms (furan-2,5-dimethanol and
`
`tetrahydrofuran diol) of HMF. The esters are more stable and
`can be readily separated, potentially making them even more
`useful than HMF itself.
`
`SUMMARY OF THE DISCLOSURE
`
`[0016] In order to address the above mentioned problems,
`the disclosure provides a method of producing substantially
`pure HMF, HMF esters or HMF ethers from a carbohydrate
`source by contacting the carbohydrate source With a solid
`phase catalyst. In the present disclosure substantially pure
`means a purity of HMF of about 70% or greater, optionally
`about 80% or greater, or about 90% or greater.
`[0017] The disclosure also provides a method of producing
`HMF esters from a carbohydrate source and organic acids. In
`one embodiment, a carbohydrate starting material is heated
`With an solvent in a column and continuously ?oWed through
`a solid phase catalyst in the presence of an organic acid to
`form a HMF ester. The solvent is removed by rotary evapo
`ration to provide a substantially pure HMF ester. In another
`embodiment, a carbohydrate is heated With the organic acid
`and a solid catalyst in a solution to form an HMF ester. The
`resulting HMF ester may then be puri?ed by ?ltration, evapo
`ration, extraction, and distillation or any combination thereof.
`[0018] In another embodiment, there is provided a method
`for oxidiZing an HMF ester to 2,5-furandicarboxylic acid
`(FDCA) by combining the HMP ester With an organic acid,
`cobalt acetate, manganese acetate and sodium bromide under
`pressure and to obtain substantially pure FDCA after ?ltra
`tion and evaporation.
`[0019] In another embodiment, there is provided a method
`of oxidiZing a reaction mixture of HMF and HMF ester to
`FDCA by the addition of cobalt acetate, manganese acetate,
`and sodium bromide under pressure and heat and isolating
`FDCA folloWing ?ltration and evaporation.
`[0020] In an alternative embodiment, there is provided a
`method of reducing an HMF ester by the addition of an
`alcohol, such as ethanol, a reducing agent, under pressure,
`heat, ?ltration and evaporation.
`[0021] Advantages of the methods as described herein are
`the high rate of conversion of carbohydrates into HMF-esters
`and derivatives. This results in a more stable form for HMF,
`and a loWer cost in materials.
`[0022] In another embodiment, there is provided a method
`for producing citrate esters from a citric acid source and an
`alcohol. Citric acid is esteri?ed With an alcohol in the pres
`ence of a catalyst on a chromatography column to produce
`trialkyl citrate or mono- and di-esters of the citric acid. In an
`alternative embodiment, a fermentation broth containing pri
`marily citric acid and residual microorganisms and fermen
`tation side products is used to produce trialkyl citrate or
`mono- and di-esters of the citric acid. In another embodiment,
`the mono- and di-esters are recycled through the catalyst and
`column to generate the triester.
`[0023] In yet an another embodiment, there is provided a
`method of preparing HMF via deacylation of an intermediate
`HMF ester. In one embodiment of this method, fructose is
`dehydrated in the presence of an organic acid and a catalyst,
`and separated via a chromatography column to produce the
`HMP ester. In an alternative embodiment, the HMP ester is
`deacylated With a solid phase catalyst in a chromatography
`column. Alternatively, the deacylation and separation of the
`HMP ester is performed using a metal alkoxide.
`[0024] In another embodiment, there is provided a method
`for the synthesis of levulinic acid or levulinic ester by con
`
`Petitioners' Exhibit 1022, Page 14 of 23
`
`

`
`US 2009/0156841A1
`
`Jun. 18, 2009
`
`tacting a carbohydrate mixture With or Without an organic
`acid present, With a solid phase catalyst under elevated tem
`perature. HMF ethers and/ or levulinate esters, Which are more
`stable than HMF may be synthesiZed and puri?ed by this
`process using an alcohol solvent. Advantages of the methods
`as described herein are the high rate of conversion of carbo
`hydrates into substantially pure HMF, HMF esters and other
`HMF derivatives.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0025] FIG. 1 illustrates a conventional autoclave reactor;
`[0026] FIG. 2 illustrates the fraction of AcHMF conversion
`in a conventional method using an autoclave reactor;
`[0027] FIG. 3 illustrates the fraction of AcHMF conversion
`according to an embodiment of the present application;
`[0028] FIG. 4 illustrates a graph of the products using the
`pulse resin test according to an embodiment of the present
`application; and
`[0029] FIG. 5 illustrates a chromatogram according to an
`embodiment of the present application.
`[0030] FIG. 6 is a 1H NMR analysis graph shoWing sub
`stantially pure 4-acetoxymethylfurfural (AcHMF).
`[0031] FIG. 7 is a 1H NMR analysis graph shoWing sub
`stantially pure 5-propionoxymethyl?1rfual.
`[0032] FIG. 8 is a 1H NMR analysis graph shoWing sub
`stantially pure 2,5-diformylfuran, 2,5-furandicarboxylic acid
`(FDCA).
`[0033] FIG. 9 is a HPLC trace shoWing the formation of
`5-acetoxymethylfurfual (AcHMF) from fructose according
`to Example 1.
`[0034] FIG. 10 is a HPLC trace shoWing the formation of
`5-acetoxymethylfurfual (AcHMF) from fructose according
`to Example 2.
`[0035] FIG. 11 is a HPLC trace shoWing the formation of
`shoWing substantially pure 5-propionoxymethylfurfual
`(PrHMF) from fructose.
`
`DETAILED DESCRIPTION
`
`[0036] The present application provides methods for syn
`thesiZing and separating hydroxymethylfurfural (HMF) and
`hydroxymethylfurfural esters from a carbohydrate source by
`contacting the carbohydrate With a solid phase catalyst.
`[0037] The use of solid phase catalysts in a chromatogra
`phy column to synthesiZe and purify HMF limits exposure
`time to heat and acid catalysts and enables synthesis at a loWer
`temperature. LoWer temperatures result in reduced energy
`costs and reduced time for heating and cooling the reaction.
`Non-limiting examples of solid phase catalysts that may be
`used in the process include acidic resins such as Amberlyst
`35, Amberlyst l5, Amberlyst 36, Amberlyst 70, Amberlyst
`131 (Rohm and Haas); LeWatit S2328, LeWatit K2431,
`LeWatit S2568, LeWatit K2629 (Bayer Company); and Dian
`ion SK104, PK228, RCP160, Relite RAD/F (Mitsubishi
`Chemical America, Inc.). Other solid phase catalysts such as
`clays and Zeolites such as CBV 3024 and CBV 5534G
`(Zeolyst International), T-2665, T-4480 (United Catalysis,
`Inc), LZY 64 (Union Carbide), H-ZSM-5 (PQ Corporation)
`can also be used. Acidic resins such as Amberlyst 35 are
`cationic, While catalysts such as Zeolite, alumina, and clay are
`porous particles that trap small molecules. Soluble catalysts
`including inorganic acids, such as H2SO4, H3PO4, HCl, and
`organic acids such as p-toluene sulfonic acid may also be
`used.
`
`[0038] An advantage of solid phase catalysts is that they do
`not dissolve in solvent and remain in the column. Depending
`on the column siZe and type of solvent used, about 30-50 g of
`resin is packed into the column. For example, the solvent
`dimethylformamide (DMF) causes Amberlyst 35 resin to
`expand in the column, and thus only about 30 g of resin is
`preferably used in a 300 mm length column. Approximately
`50 g of Amberlyst 35 resin is used When acetic acid is the
`solvent because acetic acid does not cause the resin to sWell.
`[0039] Because the synthesis of HMF is a dehydration reac
`tion, a cation exchange resin having reduced Water content is
`preferred. The presence of Water in the reaction increases
`formation of byproducts, such as, polymers and humin.
`Therefore, the maximum Water content of the solid phase
`catalyst in a column experiment is typically less than about
`20%, optionally less than about 15%, or less than about 10%.
`Many commercially available solid phase catalysts, such as,
`dry Amberlyst 35 have approximately 3% Water content.
`HoWever, solid phase catalysts With greater than 20% may be
`used under certain conditions. Solid phase catalysts having a
`Water content greater than about 20% are considered “Wet
`resins” due to their excess Water content and ability to gen
`erate Water during the reaction. If the Water content of the Wet
`resin is greater than about 20%, a solvent that is miscible With
`Water may be selected as the solvent for the reaction in order
`to remove Water from the Wet resin.
`[0040] Solvents including aprotic polar solvents are pre
`ferred because they are miscible With Water, Which helps With
`the solubility of fructose and With removing Water. An
`example of an polar aprotic solvent is acetone, Which is used
`to Wash the Wet resin and dehydrate the Wet resin before the
`reaction on the column. The resulting dehydrated resin is then
`dried under a vacuum prior to the reaction on the column. In
`addition, DMF is miscible With Water and may be used as a
`solvent to dehydrate the Wet resin on the column. The dehy
`dration of the Wet resin may include raising the temperature of
`the reaction or any suitable method for dehydrating the Wet
`resin or a combination thereof.
`[0041] An additional advantage of using a column in the
`conversion of a carbohydrate source to HMF, HMF esters or
`other HMF derivatives is the ability for the reaction to pro
`ceed and separate the product from the unreacted starting
`material or other unWanted side products that may form all in
`one step. As the reactants pass through the column, differ
`ences in the retention of the products from the starting mate
`rials Will alloW for these to separate after the reaction occurs
`in the column. As a result, the product Will elute from the
`column in a substantially pure form.
`[0042] Any carbohydrate source can be used, although
`fructose is the preferred source. Suitable carbohydrate
`sources that can be used for preparing HMF derivatives
`include, but are not limited to, hexose, fructose syrup, crys
`talline fructose, and process streams from the crystallization
`of fructose. Suitable mixed carbohydrate sources may com
`prise any industrially convenient carbohydrate source, such
`as corn syrup. Other mixed carbohydrate sources include, but
`are not limited to, hexoses, fructose syrup, crystalline fruc
`tose, high fructose corn syrup, crude fructose, puri?ed fruc
`tose, high fructose corn syrup re?nery intermediates and by
`products, process streams from crystalliZing fructose or
`glucose or xylose, and molasses, such as soy molasses result
`ing from production of soy protein concentrate, or a mixture
`thereof.
`
`Petitioners' Exhibit 1022, Page 15 of 23
`
`

`
`US 2009/0156841A1
`
`Jun. 18, 2009
`
`[0043] Synthesis of HMF esters from a carbohydrate
`source and organic acids or acid salts provides a direct path
`Way for a series of useful molecules. Aliphatic and aromatic
`esters of HMF are commercially available and have a variety
`of uses. The present process has many advantages in the
`production of HMF esters. Suitable carbohydrate sources that
`can be used for preparing HMF esters include, but are not
`limited to hexose, fructose syrup, crystalline fructose, and
`process streams from the crystallization of fructose. Suitable
`mixed carbohydrate sources may comprise any industrially
`convenient carbohydrate sources, such as corn syrup. The
`mixed carbohydrate sources include, but are not limited to,
`hexoses, fructose syrup, crystalline fructose, high fructose
`corn syrup, crude fructose, puri?ed fructose, high fructose
`corn syrup re?nery intermediates and by-products, process
`streams from crystallizing fructose or glucose or xylose, and
`molasses, such as soy molasses resulting from production of
`soy protein concentrate. In addition to the Wide variety of
`starting sources, the process can be performed With various
`organic acids including, but not limited to acetic, propionic,
`butyric, citric or diacids.
`[0044] The disclosed process minimizes and/or eliminates
`the formation of humins and polymeric by-products. If the
`reaction is not complete and HMF and or unreacted carbohy
`drate is observed in the reaction mixture, these components
`may be separated into the aqueous phase and recycled. In
`addition, the solvents can be recovered and recycled. This
`method is more bene?cial than other methods as it eliminates
`the dif?cult task of isolating substantially pure HMF for use
`as a starting source. It is a simple process, leading to a sub
`stantially pure product, Which can be used as a feeding source
`in the transformation of HMF esters to a variety of useful
`derivatives and end products. The purity of the product Will
`vary according to the particular reagents and conditions used.
`[0045] Additionally, the present application provides meth
`ods for synthesizing citrate esters, and methods of synthesiz
`ing levulinic acid or levulinic esters using a heated solidphase
`catalyst in a column, and subsequent puri?cation of the result
`ing products in a column. In an example of levulinate ester
`synthesis, a carbohydrate mixture in solution (eg 25% fruc
`tose in Acetic acid) is passed through a heated column that is
`packed With a strong acid cationic resin (e.g. Amberlyst 35).
`The temperature of the column is maintained at 75 C and the
`How rate is set to 5 mL/min. Upon the initial pass both
`Ac-HMF and Ac-levulinate acid are formed. Subsequent
`passes generate a higher ratio of Ac-levulinate to Ac-HMF.
`The concentration of acetic acid may range from >99%
`reagent grade acetic acid to 1% acetic acid in aqueous solu
`tion.
`[0046] For the synthesis of a levulinic acid, an example
`synthesis involves a carbohydrate mixture in solution (eg
`25% fructose in aqueous or DMF solution) is passed through
`a heated column that is packed With a strong acid cationic
`resin (e.g. Amberlyst 35). The temperature of the column is
`maintained at 100° C. and the How rate is set to 5 mL/min.
`Upon the initial pass both HMF and levulinic acid are formed.
`Subsequent passes generate a higher ratio of levulinic acid to
`HMF.
`[0047] Various HMF esters are selectively prepared by
`modifying the choice of solvent used in the processes of the
`invention. The amount of puri?cation and fractionation of the
`end product depends on the type of solvent used. For
`example, a continuous How of a solution of fructose dissolved
`in acetic acid through a solid phase catalyst results in the
`
`formation of substantially pure acetylated HMF (AcHMF),
`Which is a desired end product. HMF ethers and/or levulinate
`esters, Which are more stable than HMF may be synthesized
`and puri?ed by this process using an alcohol solvent.
`[0048] AcHMF has a loWer boiling point than HMF, and is
`isolated by vacuum distillation. AcHMF is also more stable
`than HMF. AcHMF is not appreciably soluble in Water mak
`ing extraction in a nonpolar organic solvents an effective
`method of puri?cation. AcHMF crystallizes in nonpolar sol
`vents at loW temperatures (e.g., hexanes around 0-25o C.).
`Moreover, HMF decomposes upon heating and produces by
`products that are not easily isolated or removed.
`
`OH
`
`HO HO
`
`O
`
`Isomerase
`
`OH
`
`OH
`
`Glucose
`
`O
`HO
`
`CHZOH
`
`H+
`
`HOHZC
`
`HO Fructose
`
`H2O
`
`HO
`
`O
`
`H
`
`O
`\ /
`
`HMF
`
`[0049] For one embodiment of the present disclosure, the
`set up of the chromatography column including a column
`packed With solid phase catalysts may be a continuous sepa
`ration Where the fructose, HMF, and solvent are fed through
`the packed column multiple times and/or the speed of addi
`tional reactants is varied. This puri?cation technique can
`include Simulated Moving Bed chromatography, Which is a
`chromatographic technique based on a How of liquid (mobile
`phase) moving countercurrent to a constant How of solid
`(stationary phase). Countercurrent ?oW enhances the poten
`tial for separation and, hence, makes the process more e?i
`cient. It also alloWs a continuous How of feed material to be
`separated, and utilizes less solvent and improves the through
`put of the equipment compared to traditional batch chroma
`tography. Alternatively, the system may include, but is not
`limited to, a simulated moving bed, continuous set up
`(CSEP), or a continuous ?oW pipe system.
`[0050] For example, in Simulated Moving Bed chromatog
`raphy, the solutes move faster than the bed and are eluted at
`the top of the column, Whereas those moving sloWer than the
`bed are brought doWn by the moving bed beloW the feed point.
`A section of the bed beloW the feed point is then heated to
`increase the elution rate of the solutes and any solute moving
`faster than the bed can be eluted through a side tube by a
`second How of gas While those solutes still moving at a sloWer
`rate than the bed continue to move doWn the column in the
`stationary phase. The higher fractions can be removed in the
`same Way by a section of the column heated to an even higher
`
`Petitioners' Exhibit 1022, Page 16 of 23
`
`

`
`US 2009/0156841A1
`
`Jun. 18, 2009
`
`temperature. In order to heat the column in Simulated Moving
`Bed chromatography, a jacketed column alloWs the mixture
`to pass heating ?uid, such as, propylene glycol, around the
`resin bed.
`[0051] In most of the reactions carried out by the methods
`described herein, the catalyst provides the necessary acidity
`for the reaction to occur. Ion exchange resins are synthetic
`polymers capable of combining or exchanging ions in a sur
`rounding solution and are used primarily for chromatography
`of organic molecules. Advantages of ion exchange resins
`include long lifetime, reusable, high selectivity and catalytic
`ability, stability, and can be used in both aqueous and non
`aqueous conditions (Rohm and Haas).
`[0052] A ?rst type of column that may be used in the dis
`closed methods is a gravity ?oW column. The reaction mix
`ture is loaded onto the top of the column, Which is heated by
`a jacket, then alloWed to sloWly ?oW through the resin, alloW
`ing maximum retention time on the column. The How rate in
`a gravity ?oW column is generally less than 1.0 mL/min, or
`typically 0.1-1.0 mL/min. Once the product is fed through the
`column, it may be reloaded for a second pass, to produce a
`higher yield of the desired product and increased purity by
`alloWing more time on the resin. The samples of the gravity
`column are collected in a large fraction or multiple fractions
`and analyZed for yield.
`[0053] Another column that may be used is a pulse column.
`The starting material is loaded on top of the resin and a
`mechanical pump is used to pump solvent onto the column to
`maintain a constant ?oW rate. The product is collected from
`the bottom of the column in timed fractions, and, therefore,
`may be analyZed for retention time, separation of products
`and reactants, as Well as total yield.
`[0054] For the column experiments, depending on the type
`of column used and the stability of the solvent, the tempera
`ture may be varied from about 70° C. to about 125° C.,
`optionally from about 75° C. to about 95° C., or optionally
`from about 80° C. to about 90° C. The How rate is typically
`kept at about 1.0 ml/minute to alloW maximum retention time
`on the column and How through to the top of the column.
`HoWever, for gravity columns, the How rate may be kept
`loWer, since it is not dependent on a mechanical source.
`Higher temperatures may be used.
`[0055] In one embodiment of the present application,
`Amberlyst 35 is packed in a heated glass jacketed column
`With fructose solubiliZed With acetic acid. The use of a con
`tinuous moving bed minimiZes exposure time of the product
`to re