WO2019170204A1

WO2019170204A1 - Synthesis of precursors of 2,5-furandicarboxylic acid

Info

Publication number: WO2019170204A1
Application number: PCT/DK2019/050078
Authority: WO
Inventors: Martin Jæger PEDERSEN; Christian Marcus PEDERSEN
Original assignee: Københavns Universitet
Priority date: 2018-03-05
Filing date: 2019-03-04
Publication date: 2019-09-12

Abstract

The present invention relates to a method for the manufacture of stable FDCA precursors from saccharide derived starting materials. More specific the invention relates to the synthesis of FDCA precursors such as alkyl 5-(hydroxymethyl)furan-2-carboxylates or 5-(hydroxymethyl)furan-2-carboxylic acid in an expedient, practical and environmental benign manner from e.g. D-glucono-δ-lactone. These bio-based monomer building blocks hold great potential in the manufacture of polymer materials.

Description

SYNTHESIS OF PRECURSORS OF 2,5-FURANDICARBOXYLIC ACID

Technical field of the invention

The present invention relates to the synthesis of a small molecule. In particular the present invention relates to the synthesis of precursors of 2,5- furandicarboxylic acid (FDCA) such as 5-(hydroxymethyl)furan-2-carboxylic acid and alkyl 5-(hydroxymethyl)furan-2-carboxylates (including methyl 5- (hydroxymethyl)furan-2-carboxylate (HMMF)) in an expedient and practical manner from a cheap bulk saccharide derived starting material such as D-glucono- d-lactone. These bio-based monomers have vast potential as building blocks in the production of e.g. polymer materials and fine chemicals.

Background of the invention

The demand for chemicals and materials obtained from the petroleum industry have been increasing despite the dwindling of the fossil resources. A large range of fine chemicals and synthetic polymers relies on the supply of a chemical feedstock originating from fossil resources, despite the environmental drawbacks that fossil resources pose to the climate. More sustainable solutions have to be invented for the future and one such solution is the synthesis of polymers from renewable natural sources decreasing the current dependence on fossil resources and lowering the production rate of CO2 to its consumption rate. Biomass derived materials have been pointed out to be one of the most promising alternatives to fossil fuels. These materials are generated from atmospheric CO2, water and sunlight through photosynthesis. Lignocellulosic biomass is the most abundant biomass on earth and holds great potential as feedstock for bio-renewable chemicals. The lignocellulosic feedstock has a great advantage over other biomass supplies because they constitute a non-edible part of the plant and does not interfere with food supplies. The major components of lignocellulosic biomass are lignin, cellulose and hemicellulose which can be converted into useful products such as sugars like glucose and xylose. 2,5-furandicarboxylic acid (FDCA) is a promising biomass based chemical used in polymers and can be obtained from 5- hydroxymethyl furfural (5-HMF) by oxidation. A wide range of both enzymatic and chemical methods have been developed for the synthesis of FDCA or its precursors.

Although various methods have been proposed for commercial scale production of FDCA the main industrial synthesis relies of synthesis of 5-HMF derived from hexoses by dehydration followed by oxidation into FDCA. The stability of 5-HMF is however low due to reactive functional groups like the aldehyde present in the molecule. Therefore, 5-HMF is not useful for storage and requires immediately conversion into more stable products posing a major drawback.

Thus, US 9,169,227 B2 describes the synthesis of HMF from hexoses under acidic conditions and high temperatures. However, this HMF synthesis is nonselective which results in low yields and considerable by-product formation (humins). The synthesis of HMMF derivatives is not described.

US 2014/0364631 discloses an ester of HMFA, i.e. HMMF. Thus, in table 10, page 22 the compound HMMF (denoted HMFC) is disclosed. No synthesis of HMMF is disclosed, including the process of the present invention.

Thus, WO 2016/141148 A1 discloses an enzymatic/microbiotic synthesis from sugars like glucose to form keto-sugars. These keto-sugars can be dehydrated under acidic conditions into furans like 5-(hydroxymethyl)furan-2-carboxylic acid (HMFA). The synthesis of alkyl esters of HMFA is not described, and yields of HMFA are very low.

Hence, an improved method for the synthesis of alternative FDCA precursors would be advantageous. In particular, a more environmental benign, efficient and/or reliable synthesis performed under mild conditions and generating high yields would be advantageous for a process scale production of bio-based FDCA precursors.

Summary of the invention

Thus, an object of the present invention relates to the synthesis of alkyl 5- (hydroxymethyl)furan-2-carboxylates, alkyl 5-(hydroxymethyl)furan-2-amides or alkyl 5-(hydroxymethyl)furan-2-carbothioate, including for example methyl 5- (hydroxymethyl)furan-2-carboxylate (HMMF), from intermediates available via the cheap precursor D-glucono-lactone. This method describes a scalable, high yield synthesis of these FDCA precursors under mild conditions.

In particular, it is an object of the present invention to provide a FDCA precursor that solves the above mentioned problems of the prior art with low yield of FDCA precursors, harsh reaction conditions and the poor stability of products such as 5- HMF. As is known in the art, 5-HMF is prone to degradation under acidic conditions with formation of humins as well as decomposition into levulinic and formic acid during its synthesis.

Thus, one aspect of the present invention relates to a method for producing a compound of Formula (I)

comprising contacting a compound of Formula (II)

with a compound of Formula (III)

H-YR¹ (III) and at least one acid,

wherein

Y is selected from the group consisting of O, NH, N R¹), and S,

R¹ is selected from the group consisting of hydrogen, an optionally substituted Ci- Cio alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and

R², R³ and R⁴ are an alcohol protecting group.

The present inventors surprisingly found that the method of the present invention suppresses the formation of humins and other by-products resulting in higher yield of the desired bio-based precursors of FDCA, such as HMMF. The method uses cheap starting materials and a high recovery of the involved reagents are achieved. Finally, the present method can readily be performed on large scale. Brief description of the figures

Figure 1 shows the synthesis of furans of Formula (I) from protected lactones of Formula (II) and protic compounds of Formula (III).

Figure 2 shows the synthesis of lactones of Formula (II) from protected glucono- lactones of Formula (IV).

Figure 3 shows the synthesis of protected glucono-lactones of Formula (IV) from the glucono-lactone of Formula (V), and Figure 4 shows the schematic conversion of biomass feedstock into useful monomer building blocks, including HMMF as an example of the FDCA precursors of the present invention. HMMF is shown to also be the precursor of other useful chlorinated and reduced compounds. The present invention will now be described in more detail in the following. Detailed description of the invention

Definitions

Prior to discussing the present invention in further details, the following terms and conventions will first be defined :

Acid: In the present context acid refers to either Bronsted or Lewis acids. By Bronsted acid is meant a molecular entity capable of donating a proton. By Lewis acid is meant any moiecuiar entity that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base.

Base: In the present context base refers to either Bronsted or Lewis bases. By Bronsted base is meant a molecular entity capable of accepting a proton. By Lewis base is meant any molecular entity that is an electron-pair donor and therefore able to react with a Lewis acid to form a Lewis adduct, by sharing the electron pair- furnished by the Lewis base. Bronsted acid and bases are also referred to as Bronsted-Lowry acid and bases.

Solvent: In the present context a solvent is the liquid in which a solute is dissolved to form a solution or partly dissolved to form a dispersion.

In the present context a co-solvent is any solvent acting in conjunction with another solvent to aid in dissolving a solute. Solvents may act as reactants and vice versa.

Ci-Cio Alkyl: Univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom -C„H₂„_+I, where n is 1-10, i.e. 1-10 carbon atoms are comprised. Ci-Cio alkyls may be linear or branched. The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (/7-alkyl) groups H(CH₂)„. The groups RCH₂, R₂CH (R ¹ H), and R₃C (R ¹ H) are primary, secondary and tertiary alkyl groups, respectively.

Cx-Cy, such as Ci-Cio generally refers to the total number carbon atoms also for alkenyls, alkynyls, acyls, alkoxycarbonyls etc., which all have their usual meaning. Ci-Cio alkenyls and alkynyls may be linear or branched. Optionally substituted: In the present context optionally substituted in the broadest sense refers to a group or moiety which may optionally substituted further substituents while remaining within its basic category. Thus, an optionally substituted Ci-Cio alkyl, may comprise further substituents, including for example further alkyl groups, halogens, aryls, heteroaryls and silyl groups.

SYNTHESIS OF COMPOUNDS OF FORMULA (I)

The first aspect of the present invention relates to a method for producing a compound of Formula (I)

comprising contacting a compound of Formula (II)

with a compound of Formula (III)

H-YR¹ (III)

and at least one acid,

wherein

Y is selected from the group consisting of O, NH, N(R^!), and S,

R¹ is selected from the group consisting of an optionally substituted Ci-Cio alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and R², R³ and R⁴ are an alcohol protecting group.

An alternative aspect of the present invention relates to a method for producing a compound of Formula (I)

comprising contacting a compound of Formula (II)

with a compound of Formula (III)

H-YR¹ (III)

and at least one acid,

wherein

Y is selected from the group consisting of O, NH, I ^R¹), and S,

R², R³ and R⁴ are an alcohol protecting group.

In this alternative aspect when R¹ is hydrogen, the compound of Formula (I) may be 5-(hydroxymethyl)furan-2-carboxylic acid (HMFA). Also in this aspect the compound of formula (III) may be water. In principle any alcohol protecting group known to a person skilled in the art, which is labile under the acidic conditions used in the formation of a compound of Formula (I) may be employed. Thus, in a preferred embodiment R², R³ and R⁴ are an alcohol protecting group independently selected from the group consisting of optionally substituted Ci-Cio acyl, optionally substituted Ci-Cio alkoxycarbonyl, optionally substituted Ci-Cio alkylsilyl, tert-butyl, optionally substituted Ci-Cio alkoxythiocarbonyl, optionally substituted Ci-Cio N-alkylaminocarbonyl,

methoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, borate ester, boronate ester. Preferably the alcohol protecting groups R², R³ and R⁴ are independently selected from optionally substituted C1-C4 acyl, optionally substituted C1-C4 alkoxycarbonyl. In an especially preferred embodiment R², R³ and R⁴ are acetyl. Acetyl has proven a facile protection group in the method of the present invention which provides high yields and is readily separated from the product after de-protection due to e.g. its volatility.

In another embodiment H-YR¹, the compound of Formula (III), is used as solvent, and if so, preferably no further solvents are present. In this embodiment high yields are provided due to large excess of H-YR¹, and thus comparably small amounts of competing nucleophiles. In another embodiment H-YR¹ (III) may be used together with a co-solvent to help dissolution of the reactants. Other co- solvents can be common organic solvents used in the art, preferably non-reactive solvents, such as but not limited to THF, DMF, DCM, carbon tetrachloride, chloroform, chlorobenzene, toluene, Et20, acetone, MeCN, 1-butanol, EtOAc, 1,2- dichloroethane, MTBE, NMP, MeOH, EtOH, 1-propanol, 2-propanol, 1,4-dioxane, DME, DMSO, ethylene glycol, diglyme, o-xylene, m-xylene, p-xylene, petroleum ether, pentane, hexane, HMPA, HMPT. In one preferred embodiment the percentage of water present during the process of the present invention is less than 10%, such as less than 5%, 2%, 1%, 0.1%, such as less than 0.01% by volume as compared to the total volume of the process solution. Preferably, water is not present during the reaction process. In another preferred embodiment where 5-(hydroxymethyl)furan-2-carboxylic acid (HMFA) is needed water is present.

In a preferred embodiment Y is O. In another preferred embodiment R¹ is C1-C10 alkyl, such as C1-C3 alkyl. In a more preferred embodiment Y is O and R¹ is C1-C10 alkyl. In an even more preferred embodiment Y is O and R¹ is C1-C3 alkyl. In a more preferred embodiment H-YR¹ is selected from the group consisting of methanol, ethanol, H2O and propanol or combinations thereof. Embodiments where Y is O and R¹ is C1-C10 alkyl have proven particularly advantageous, resulting in facile reactions and providing high yields and high reagent recovery.

Depending on the choice of H-YR¹ (III) different products of Formula (I) is obtained. In an embodiment of the invention the compound of Formula (I) is methyl 5-(hydroxymethyl)furan-2-carboxylate (HMMF), ethyl 5- (hydroxymethyl)furan-2-carboxylate, propyl 5-(hydroxymethyl)furan-2- carboxylate or 5-(hydroxymethyl)furan-2-carboxylic acid (HMFA). In a highly preferred embodiment the compound of Formula (I) is methyl 5- (hydroxymethyl)furan-2-carboxylate (HMMF).

In principle, any acid capable of aiding in cleavage of the alcohol protecting groups, cleavage of the lactone in the compound of Formula (II) and dehydration to obtain a furan of Formula (I) can be used. Hence, in one embodiment, the at least one acid is selected from the group consisting of Bronsted acids and Lewis acids. In an embodiment of the present invention, the at least one acid is selected from the group consisting of mineral acids and Lewis acids, preferably mineral acids. The acid may be completely dissolved in the mixture to form a

homogeneous mixture or may be insoluble or only partially soluble to form a heterogeneous mixture.

In a preferred embodiment the acid is selected from the group consisting of HCI, HBr, HI, HF, H3PO4, H2SO4, HNO3, H3BO3, HCICU, TfOH, MsOH, TsOH,

polyphosphoric acid, BF3-OEt2, I2, FeCb, Nafion, Amberlite IR-120, and zeolites. Even more preferably the acid is selected from the group consisting of HCI, HBr, HF, H3PO4, H2SO4, HNO3, TfOH, Amberlite IR-120, BF₃-OEt₂, I2, FeCb. The acid may be added to the reaction mixture as a concentrated solution or from a more dilute solution with any desired molarity or may be generated in situ. Thus, in yet another embodiment of the invention HCI is used as acid and generated in situ by addition of acetyl chloride AcCI to the solution. The reaction may be performed at different temperatures and reaction times depending on the choice of acid, H-YR¹ (III) and co-solvents used. Hence, in an embodiment the method for producing a compound of Formula (I) is performed at a temperature in the range of 0-200 °C, such as 5-150 °C, 10-120 °C, 15-100 °C, 20-80 °C, 25-70 °C, 30-65 °C, 35-60 °C, such as preferably 40-65 °C. The heating means used may be chosen from any method know to a person skilled in the art such as conventional heating or microwave heating. The reaction may be performed under both innate conditions and open to air. In an embodiment of the present invention the reaction may be performed in a closed system under pressure such that solvents with lower boiling points are allowed to reach higher reaction temperatures.

SYNTHESIS OF INTERMEDIATE COMPOUNDS OF FORMULA (II)

In a further embodiment of the present invention the compound of Formula (II) is produced by a method comprising contacting the compound of Formula (IV)

with a base, wherein R², R³, R⁴, and R⁵ are an alcohol protecting group. The present inventors found that by appropriate choice of reaction conditions the protected substrate of Formula (IV) could be converted into the enone of Formula (II) by elimination of a protected alcohol, in high yields.

Preferably, R², R³, R⁴ and R⁵ are an alcohol protecting group independently selected from the group consisting of optionally substituted Ci-Cio acyl, optionally substituted Ci-Cio alkoxycarbonyl, optionally substituted Ci-Cio alkylsilyl, tert- butyl, optionally substituted Ci-Cio alkoxythiocarbonyl, optionally substituted Ci- Cio N-alkylaminocarbonyl, methoxymethyl, benzyloxymethyl, 2- tetrahydropyranyl, benzyl, 4-methoxybenzyl, borate ester, boronate ester. Acetyl and other short chain carboxy protecting groups are advantageous, as they may be recovered, e.g. by distillation when cleaved, allowing for easier recovery of reagents and purification of products. Hence, R², R³, R⁴ and R⁵ are preferably Ci- C3 acyl, most preferably acetyl.

For the present method of producing the compound of Formula (II) the base may be an organic base or an inorganic base covering a range of different base strengths (p/ b). Preferably, the base may be selected from the group consisting of but not limited to NaOAc, KOAc, LiOAc, Et3N, pyridine, collidine, TMP, DBU,

CaCOs, CeCOs, U2CO3, Na₂C0₃, K2CO3, UHCO3, NaHCOs, KHCOs, U3PO4, Na₃P0₄, K3PO4, U2HPO4, Na₂HP04, K2HPO4, CaO, CaOH₂, NaOH, KOH, zeolites, Amberlite IRA-400. In a particular preferred embodiment the base is NaOAc. Preferably the base is added in catalytic amounts, such as less than 10 mol %, such as less than 5 mol %, less than 2 mol %, preferably 5 mol %. The inventors found that 93 % of the base could be recovered by filtration and reused when NaOAc was used.

The elimination to form the enone of Formula (II) may be conducted at different temperatures and reaction times depending on the choice of base and solvents used. Thus, in an embodiment the elimination reaction to form compound of Formula (II) the method is performed at a temperature in the range of 0-200 °C, such as 5-180 °C, 10-170 °C, 15-160 °C, 20-150 °C, 25-140 °C, 30-130 °C, 35- 120 °C, 40-110 °C, 45-100 °C, 50-90 °C, 55-80 °C such as preferably 55-65 °C. The method may be performed in a solvent, or without the use of solvent (neat).

SYNTHESIS OF INTERMEDIATE COMPOUNDS OF FORMULA (IV)

In a preferred embodiment of the present invention the compound of Formula (IV) may be produced by a method comprising contacting the compound of Formula (V)

with a reagent selected from the group consisting of Ci-Cio acyl halide, Ci-Cio acid anhydride, isopropenyl acetate, C1-C10 alkoxycarbonyl halide, and C1-C10 alkylsilyl halide, di-ferf-butyl dicarbonate, 2-methylpropene, optionally substituted C1-C10 alkoxythiocarbonyl halide, optionally substituted C1-C10 N-alkylaminocarbonyl halide, methoxymethyl halide, benzyloxymethyl halide, dihydropyran, benzyl halide, 4-methoxybenzyl halide, and aryl boronic acids, such as phenylboronic acid, or 4-(trifluoromethyl)phenylboronic acid.

Depending on the reagent used a base or acid may further be added to facilitate the reaction. In a particularly preferred embodiment the alcohols in the compound of Formula (V) are protected with an acetyl group. Suitable reagents for this protection is AC2O, acetyl halide or isopropenyl acetate. Other equivalents for formation of esters as alcohol protecting groups known in the art may be used. Thus in an embodiment the alcohols may be protected using an acid in the presence of a coupling reagent such as DCC, HATU, CDI, PyBOB or another coupling reagent known in the art. In principle any activated ester can be used in the coupling for protection of compound (V) such as a pentafluorophenyl ester, succinimidyl esters or other equivalents known in the art. In yet another embodiment of the invention the condensation between an ester and/or acid and the alcohols in compound (V) is performed under acidic catalysis optionally with removal of alcohol and/or water with means such as reflux in a Dean Stark apparatus or equivalent means known in the art. The method may be performed in a solvent, or without the use of solvent (neat). In a particularly preferred embodiment of the invention the alcohols in compound (V) is condensed with an ester, such as the vinyl ester isopropenyl acetate. The inventors found that the alcohols in compound (V) could be protected using AC2O in the presence of catalytic amounts of iodine (<0.2 mol %).

Thus, in a preferred embodiment the compound of Formula (V) is reacted with a Ci-Cio acid anhydride and a lewis acid, such as acetic anhydride and iodine. In another preferred embodiment the compound of Formula (V) is reacted with a Ci- Cio acid anhydride and a bronsted acid such as acetic anhydride and H2SO4 or Amberlite IR-120. Preferably the lewis or bronsted acid is present in catalytic amounts, such as less than 10 mol %, such as less than 5 mol %, less than 2 mol %, less than 1 mol %, less than 0.5 mol % such as less than 0.2 mol %.

In a preferred embodiment the method is performed in neat acetic anhydride. An advantage of using acetic anhydride is that the resulting NaOAc can be filtered off and recovered and the formed acetic acid and remaining AC2O may be distilled off and recovered. The compound of Formula (V) may be completely dissolved in the acetic anhydride or partly dissolved to form a suspension. In a preferred embodiment the compound of Formula (V) is suspended in only a slight excess of acetic anhydride. In the present context a slight excess should be understood as a little more than needed for a theoretical complete acetylation of all four alcohols in compound (V) (i.e. 4 eq.). Preferably the acetic anhydride is present in 15-20 eq., such as 10-15 eq., such as 7-10 eq., more preferably 4-5.5 eq. of acetic anhydride is present. In another preferred emdodiment the method is performed in a mixture of acetic acid and AC2O (< 4 eq.) such that acetylation is partly achieved by acetic acid. The advantage of this is less use of AC2O.

The inventors further found that the alcohols in compound (V) could

advantageously be protected by condensation with an ester in the presence of catalytic amounts of acid. Thus, in the most preferred embodiment the compound of Formula (V) is reacted with isopropenyl acetate in the presence of H2SO4.

Preferably the acid is present in catalytic amounts, such as less than 10 mol %, such as less than 5 mol %, less than 2 mol %, less than 1 mol %, less than 0.5 mol %, such as less than 0.2 mol %, less than 0.1 mol% such as 0.05 mol % as compared to the amount of compound (V). The isopropenyl acetate may be present in amounts of e.g. 2-20 equivalents, such as 2-10 equivalents, such as 2- 5 equivalents as compared to compound (V). In an embodiment of the invention the lactone of Formula (V) may be in the closed form as depicted or in its hydrolysed, open form. Depending on the conditions used, the open and closed form may be in equilibrium with each other. Thus, in an embodiment starting from an open form the closed lactone may be formed in situ or vice versa depending on the conditions used. Thus, the lactone of Formula (V) is interchangeable with the hydrolysed form, e.g. D-gluconic acid.

The inventors found that the method for producing a compound of Formula (IV) and subsequent elimination to form the compound of Formula (II) can

advantageously be performed in a one-pot reaction, in high yield. Thus, in a preferred embodiment the method of producing the compound of Formula (IV) and the subsequent method of producing the compound of Formula (II) is performed in one pot, i.e. preferably the compound of Formula (IV) is not subjected to purifications steps prior to using it as an intermediate in the method of making the compound of Formula (II). In other words a crude compound of Formula (IV) is used in the method of making the compound of Formula (II). This method provides high yields of compounds of Formula (II) from the starting compound of Formula (V), and time consuming purifications steps such as column chromatography are avoided. The inventors further found that all the steps in the method of producing a compound of Formula (I) starting from a compound of Formula (V) may be performed on the crude intermediates (i.e. crude compound of Formula (IV) and (II)) such that only purification is performed on the final product (i.e. a compound of Formula (I)). The final product may be purified by silica gel chromatography, vacuum distillation or sublimation.

The alcohol protection of compound (V) may be performed at different

temperatures depending on the protection conditions used. In an embodiment the method is performed at a temperature in the range of 0-200 °C, such as 5-180 °C, 10-170 °C, 15-160 °C, 20-150 °C, 25-140 °C, 30-130 °C, 35-120 °C, 40-110 °C, 45-100 °C, 50-90 °C, 55-80 °C such as 10-40 °C, 15-35 °C, such as preferably 20-30 °C.

The compound of Formula (V) is obtainable from aldohexose sugars such as allose, altrose, glucose, mannose, gulose, idose, galactose and talose by oxidation of the lactol to the lactone. In a preferred embodiment of the invention the compound of Formula (V) is D-glucono-6-lactone. D-glucono-6-lactone (GDL) is easily obtainable from D-glucose, leading to very low costs of this precursor.

The furans of Formula (I) may be further converted into other useful furan compounds. Thus in an embodiment the compound of Formula (I) is further converted into methyl 5-(chloromethyl)furan-2-carboxylate or methyl 5- (bromomethyl)furan-2-carboxylate by a suitable halogenation reaction. In another embodiment of the invention the compound of Formula (I) is further converted to 2,5-furandicarboxylic acid (FDCA). FDCA may be obtained from the compound of Formula (I) by oxidation. FDCA can then be used as a bio-based monomer as an alternative to terephthalic acid in polyethylene type polyesters. (Moreau et. al in Topics in Catalysis Vol 27, Nos. 1-4, 2004, 11-30).

It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.

All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples.

EXAMPLES EXAMPLE 1 : Synthesis of 2.4.6-tri-0-acetyl-D-ervf/7ro-hex-2-enono- 1.5-lactone ill

Method 1 : adapting the procedure of Pedersen, C. Carbohydr. Res.315, 192-197 (1999). D-glucono-6-lactone (1.00 g) was suspended in 8 mL acetic anhydride at 23 °C and stirred for one hour. The resulting mixture was then cooled in an icebath to 0 °C before 0.80 mL trimethylamine was added slowly, to facilitate the protection of the alcohols with acetyl. Subsequently the reaction mixture was allowed to reach 23 °C over the next four hours to facilitate the elimination. Hereafter, the mixture is concentrated, dissolved in ethyl acetate and washed twice with saturated NaHCCb, H2O and brine, the organic phase was dried with Na2S0₄, filtered, concentrated and purified by column chromatography (1 : 3, diethyl ether/petroleum ether) to yield compound 1 (1.268 g, 79 %).

Method 2: D-glucono-b-lactone (10.00-10.14 g) was suspended in acetic anhydride (27.5-26.5 mL, 5.5 eq) together with iodine (21-12.6 mg, 0.15-0.087 mol%) and stirred overnight at 23 °C or for two hours at 50°C. The resulting clear mixture was added NaOAc (5.51 g, 1.2 eq) and heated to 60 °C, after 2.5-3.2 hours ^ NMR indicates full conversion (>95%). The reaction mixture was then concentrated, dissolved in either EtOAc or Et20, filtered and concentrated to yield yellow syrup of 1, which was used further as is.

Method 3: D-glucono-b-lactone (10.06 g) was suspended in acetic anhydride (22 mL, 4.2 eq) together with H2SO4 (95%, ~30 pL, 1 mol%) and stirred at 22 °C and raised to 80 °C. After 10 minutes the reaction was complete and to the resulting clear mixture was added NaOAc (340 mg, 7.3 mol%) and heated to 90 °C, after 4.5 hours NMR indicates >95% conversion. The reaction mixture was used further as is.

*H NMR (500 MHz, CDCI3) d 6.44 (d, J³ ₃,4 = 4.2 Hz, 1H, H3), 5.62 (dd, J³ ₄,s = 5.8 Hz, 1H, H4), 4.76 (m, 1H, H5), 4.39 (dd, J²6a,6b = 12.4 Hz, J³ ₅,6a = 4.9 Hz, 1H, H6a), 4.30 (dd, J³s,6b = 4.4 Hz, 1H, H6b), 2.26 (s, 3H, CH₃ ^0Ac), 2.13 (s, 3H, CH₃ ^0Ac), 2.10 (s, 3H, CH₃°^Ac). ¹³C NMR (126 MHz, CDCb) d 170.5/ 169.8/ 168.3 (3C, CO^Ac), 157.3 (Cl), 139.8 (C2), 126.2 (C3), 78.0 (C5), 64.3 (C4), 62.1 (C6), 20.8/ 20.8/ 20.5 (3C, CH₃ ^Ac). Identical to reported ^ NMR² and ¹³C NMR¹ spectra.

The above method 1 and 2 are two examples of producing compound of Formula (II) in one pot from glucono-lactone.

EXAMPLE 2: Synthesis of methyl 5-(hvdroxymethyl)furan-2-carboxylate (HMMF) (2) from purified compound 1.

(starting from isolated and purified compound 1 of method 1 in EXAMPLE 1) : To a solution of 4 mL MeOH and 1 (147 mg, 0.51 mmol) at 22 °C, was added acetyl chloride (20 pL, 0.5 eq). After stirring overnight TLC indicated full conversion, the reaction mixture was added silica and concentrated on this, purified by column chromatography (1 :6®1 : 5 acetone/toluene) to yield compound 2 as yellowish oil (44.2 mg, 55 %). bp 121-124 °C (2.1-2.4*10 ¹ mbar), *H NMR (500 MHz, CDCb) d 7.13 (d, J³ _3r4 = 3.5 Hz, 1H, H3), 6.41 (dt, J = 0.8 Hz, 1H, H4), 4.68 (d, J³CH₂,OH = 6.2 Hz, 2H, _CH2 ^hydrox^yme^thyi)_{; 3 8}g (_{S; 3H;} CH₃ ^ester), 2.14 (t, 1H, OH). ¹³C NMR (126 MHz, CDCb) d 159.3 (CO^ester), 158.4 (C5), 144.2 (C2), 119.0 (C3), 109.6 (C4), 57.7 (CHz^^^y^^y'), 52.1 (CH₃ ^ester)· Identical to reported

NMR³'⁴ and ¹³C NMR³ spectra.

The present reaction represents an example of performing the method of the main aspect of the invention, i.e. the last step towards e.g. HMMF, at high yield.

EXAMPLE 3: Synthesis of methyl 5-fhvdroxymethvnfuran-2-carboxylate fHMMF^’) (2) from D-alucono-d-lactone via crude compound 1 fl gram scaleT

Starting from, D-glucono-5-lactone (1.01 g), acetic anhydride (8 ml_), iodine (6.8 mg) and NaOAc (533 mg), compound 1 was produced as in method 2 of EXAMPLE 1. The resulting crude syrup of compound 1 was dissolved in 10 mL MeOH and to this acetyl chloride (50 pL, 0.12 eq) was added. After stirring for 3 days TLC indicated full conversion, the reaction mixture was concentrated and purified by column chromatography (1 : 6 acetone/toluene) to yield compound 2 as yellowish oil (612 mg, 69 %). bp 121-124 °C (2.1-2.4*10 ¹ mbar), *H NMR (500 MHz, CDCb) d 7.13 (d, J³ ₃A = 3.5 Hz, 1H, H3), 6.41 (dt, J = 0.8 Hz, 1H, H4), 4.68 (d, J³CH₂,OH = 6.2 Hz, 2H, _CH2 ^hydrox^yme^thyi)_{; 3 8}g (_{S; 3H;} CH₃ ^ester), 2.14 (t, 1H, OH). ¹³C NMR (126 MHz, CDCb) d 159.3 (CO^ester), 158.4 (C5), 144.2 (C2), 119.0 (C3), 109.6 (C4), 57.7 (CHz^^^y^^y'), 52.1 (CH₃ ^ester)· Identical to reported

NMR³' and ¹³C NMR³ spectra.

The yield in the present example is the total yield of HMMF over three steps stemming from glucono-lactone.

EXAMPLE 4: Synthesis of methyl 5-fhvdroxymethvnfuran-2-carboxylate fHMMF^’) (2) from D-qlucono-d-lactone via crude compound 1 (10 gram scale).

Starting from D-glucono-5-lactone (10.03 g), acetic anhydride (70 ml_), iodine (25 mg) and NaOAc (5.50 g) compound 1 was produced as in method 2 of EXAMPLE 1. The crude syrup of compound 1 was dissolved in 50 mL MeOH and to this acetyl chloride (0.40 mL, 0.10 eq) was added. After stirring for 20 hours at 23 °C, the temperature was raised to 50 °C and TLC indicated full conversion after 24 hours at this temperature. The reaction mixture was concentrated and purified by vacuum distillation to yield compound 2 as yellow oil (4.997 g, 56.8 %). bp 121-124 °C (2.1-2.4*10 ¹ mbar), *H NMR (500 MHz, CDCb) d 7.13 (d, J³ ₃A = 3.5 Hz, 1H, H3), 6.41 (dt, J = 0.8 Hz, 1H, H4), 4.68 (d, J³CH₂,OH = 6.2 Hz, 2H, _{CH 2}hydroxymethyi)_{; 3 8}g (_{S; 3H;} CH₃ ^ester), 2.14 (t, 1H, OH). ¹³C NMR (126 MHz, CDCb) d 159.3 (CO^ester), 158.4 (C5), 144.2 (C2), 119.0 (C3), 109.6 (C4), 57.7 (CHz^^^y^^y'), 52.1 (CH₃ ^ester)· Identical to reported

NMR³'⁴ and ¹³C NMR³ spectra.

The yield in the present example is the total yield of HMMF over three steps stemming from glucono-lactone in a larger scale than in example 3.

EXAMPLE 5: screening of acids, acid loading and reaction conditions

A variety of acids were tested adapting the method of example 4, while varying the acid used. Reaction time and yields were measured as reported in table 1.

Table 1. Adapting the method of example 4, starting from

D-glucono-b-lactone (10 g), acetic anhydride (27 ml_), iodine

(21 mg) and NaOAc (5.5 g). The crude syrup was dissolved

to 55 ml_ in MeOH and divided into 5 separate reaction

vessels.

Loading Reaction time^b

Entry³ Acid Yield^c

(mol%) (days)

1 H2SO4 10 <4 47

2 HCI 10 4 44

3 IR-120 (H) 300 % ^w/w >10 ^e40

4 BFs-EtzO 10+50^d 6 39

5 HBr 10 4 34

a All reactions were run at 22 °C, ^b Based on daily TLC

analysis, ^c Based on a fifth of the starting D-glucono-d- lactone, ^d after five days additional 50 mol% catalyst was

added and TLC indicated full conversion overnight, ^e 5- (hydroxymethyl)furan-2-carboxylic acid (249mg, 16%) was

also isolated from this reaction. As shown good yields could be obtained using various acids at loadings as low as 10% and at room temperature conditions. Table 2. Adapting the method of example 4, starting from D-glucono-d- lactone (10 g), acetic anhydride (27 ml_), iodine (13 mg) and NaOAc (5.5 g).

The crude syrup was dissolved to 55 ml_ in MeOH and divided into 10 separate reaction vessels.

Reaction time Con- Yield^b

Loading

Entry Acid (days)³ version

(mol%)

22 °C 50 °C (%) (%)

1 HCI 20 <2 >99 30^c

3 TfOH 20 <2 >99 26^c

4 12 10 1 >99 21^c'^e

5 FeCh 20 1 >99 14^c

6 Nafion 20 % w/w 6 >99 14^c'^d

7 H3PO4 20 >6 >99 3^C

a Based on daily TLC analysis, ^b based on

NMR, with methyltriphenylsilane as a standard. Note: reaction mixtures were left for 40 days before the

following work-up procedures; ^c reaction mixture was diluted with 10 ml_

CH2CI2, and washed with 1 : 1 FhO/saturated NaHCCb solution. The FteO-phase was extracted twice with 10 ml_ CH2CI2 and the combined organic washes were dried with MgSCM and concentrated under reduced pressure. From the resulting crude syrup a sample was dissolved in a standard solution of

methyltriphenylsilane in CDC and the yield of 2 was calculated. ^d Additional to the work-up procedure is first a filtration of the diluted solution trough a pad of silica. ^e Addition of sodium sulfite during washing.

Example 5 demonstrates that very high conversions rates are achieved with 10 to 20 mol% acid loading at 22-50 °C, with a variety of Bronsted and Lewis Acids, with good overall yields for the three steps from glucono-lactone to HMMF.

Example 6: Synthesis of methyl 5-(hvdroxymethvnfuran-2-carboxylate PHMME) (2) from D-alucono-5-lactone (20 gram scale).

D-glucono-5-lactone (1.5 g) was suspended in isopropenyl acetate (10 eq.) then a catalytic amount of H2SO4 (95 %) was added and stirred overnight at room temperature. The resulting clear mixture was added NaOAc (1.2 eq.) and heated to 60°C, after 5 hours ^-NMR indicate >95% conversion. The NaOAc was filtered, washed with cold acetone and the filtrate was concentrated. The resulting yellow syrup was dissolved in MeOH and to this acetyl chloride (0.1 eq.) was added. After stirring at 60°C overnight the reaction mixture was concentrated and purified to afford methyl 5-(hydroxymethyl)furan-2-carboxylate (2) as yellow oil in 46 % yield. EXAMPLE 7: Synthesis of ethyl 5-(hvdroxymethyl)furan-2-carboxylate (3)

A crude syrup of 1 (1.180 g) was dissolved in 10 mL Absolut EtOH and to the resulting mixture was added AcCI (58 pL, 0.2 eq) at 22 °C. After 3 days, TLC analysis indicated full conversion of the starting material and the reaction mixture was concentrated, dissolved in acetone and concentrated on silica. This material was purified by column chromatography (1 : 5®1: 3®4: 6 acetone/toluene) to give the title compound 3 (240 mg, 34 %). *H NMR (500 MHz, CDCb) d 7.11 (d, J = 3.5 Hz, 1H, H3), 6.40 (d, J = 3.5 Hz, 1H, H2), 4.67 (s, 2H, H6), 4.35 (q, J = 7.1 Hz, 2H, Hll^Et), 2.24 (br s, 1H, H7^0H), 1.36 (t, J = 7.1 Hz, 3H, H12^Et). ¹³C NMR (126 MHz, CDCb) d 158.9 (Cl), 158.3 (C8^C0), 144.5 (C4), 118.8 (C3), 109.5 (C2), 61.2 (Cll^Et), 57.7 (C6), 14.5 (C12^Et). HRMS (ESP-TOF) m/z for C₈HioNa04⁺ (MNa⁺) calculated : 193.0471; found : 193.0478. Besides 3, the following was also isolated, 5-(hydroxymethyl)furan-2-carboxylic acid (98 mg, 17 %), 2, 4-di-0-acetyl-D-erythro-hex-2-enono-l, 5-lactone (26 mg) and 2-0-acetyl-D-erythro-hex-2-enono-l, 5-lactone (56 mg). EXAMPLE 8: Synthesis of butyl 5-fhvdroxymethvnfuran-2-carboxylate

A crude syrup of 1 (516 mg) was dissolved in 5.0 mL 1-butanol and to the resulting mixture was added AcCI (60 pL) at 22 °C, the mixture was initially heated to allow the starting material to fully dissolve. After 2 days TLC analysis indicated full conversion of the starting material and the reaction mixture was concentrated, dissolved in acetone and concentrated on silica. This material was purified by column chromatography (1 : 6®1 : 5 acetone/toluene) to give 5- (hydroxymethyl)furan-2-carboxylic acid (65 mg, 26 %) and the title compound 4 (133 mg, 37 %).

*H NMR (500 MHz, CDCb) d 7.11 (d, J = 3.5 Hz, 1H, H3), 6.41 (d, J = 3.4 Hz, 1H, H2), 4.67 (d, J = 5.3 Hz, 2H, H6), 4.30 (t, J = 6.7 Hz, 2H, Hll^nBu), 2.11 (br t, J = 5.3 Hz, 1H, H7^0H), 1.72 (p, J = 6.8 Hz, 2H, H12^nBu), 1.44 (h, J = 7.4 Hz, 2H, H13^nBu), 0.96 (t, J = 7.4 Hz, 3H, H14^nBu). ¹³C NMR (126 MHz, CDCb) d 159.0 (Cl), 158.3 (C8^C0), 144.5 (C4), 118.7 (C3), 109.5 (C2), 65.0 (Cll^nBu), 57.8 (C6), 30.9 (C12^nBu), 19.3 (C13^nBu), 13.9 (C14^nBu). HRMS (ESP-TOF) m/z for CioHi₄NaC>4⁺ (MNa⁺) calculated : 221.0784; found : 221.0792.

EXAMPLE 9: Synthesis of sec-Butyl 5-(hvdroxymethyl)furan-2-carboxylate (5)

A crude syrup of 1 (476 mg) was dissolved in 5.0 mL 2-butanol and to the resulting mixture was added AcCI (60 pL) at 22 °C, the mixture was initially heated to allow the starting material to fully dissolve. After 2 days, with little conversion, the reaction mixture was heated to 70 °C overnight and TLC analysis indicated full conversion of the starting material. The mixture was concentrated, dissolved in acetone and concentrated on silica. This material was purified by column chromatography (1 : 6®1 : 5 acetone/toluene) to give 5-(hydroxymethyl)furan-2- carboxylic acid (69 mg, 29 %) and the title compound 5 (49 mg, 15 %). *H NMR (500 MHz, CDCb) d 7.10 (d, J = 3.4 Hz, 1H, H3), 6.40 (d, J = 3.4 Hz, 1H, H2), 5.06 (h, J = 6.3 Hz, 1H, Hll^sBu), 4.67 (s, 2H, H6), 1.77 - 1.57 (m, 2H, H12^sBu), 1.31 (d, J = 6.3 Hz, 3H, H14^sBu), 0.95 (t, J = 7.5 Hz, 3H, H13^sBu). ¹³C NMR (126 MHz, CDCb) d 158.6 (Cl), 158.0 (C8^C0), 144.7 (C4), 118.3 (C3), 109.4 (C2), 73.2 (Cll^sBu), 57.6 (C6), 28.9 (C12^sBu), 19.6 (C14^sBu), 9.7 (C13^sBu). HRMS (ESP-TOF) m/z for CioHi₄NaC>4⁺ (MNa⁺) calculated : 221.0784; found : 221.0792.

EXAMPLE 10: Synthesis of Allyl 5-(hvdroxymethyl)furan-2-carboxylate (6)

A crude syrup of 1 (505 mg) was dissolved in 5.0 mL allyl alcohol and to the resulting mixture was added AcCI (60 pL) at 22 °C. After 2 days, TLC analysis indicated full conversion of the starting material. The mixture was concentrated, dissolved in acetone and concentrated on silica. This material was purified by column chromatography (1 : 6®1 : 5 acetone/toluene) to give 5-(hydroxymethyl)furan-2-carboxylic acid (48 mg, 19 %) and the title compound 6 (82 mg, 25 %).

*H NMR (500 MHz, CDCB) d 7.16 (d, J = 3.4 Hz, 1H, H3), 6.42 (d, J = 3.4 Hz, 1H, H2), 6.00 (ddt, J = 17.2, 10.5, 5.8 Hz, 1H, H12^AN), 5.40 (dq, J = 17.2, 1.5 Hz, 1H, H13^{All trans}), 5.29 (dq, J = 10.3, 1.3 Hz, 1H, H13^{AI| C/S}), 4.80 (dt, J = 5.8, 1.4 Hz, 2H,

H11^AN), 4.68 (d, J = 5.7 Hz, 2H, H6), 2.03 (t, J = 6.3 Hz, 1H, H7^0H). ¹³C NMR (126 MHz, CDCb) d 158.5 (2C, Cl, C8^C0), 144.2 (C4), 131.9 (C12^AN), 119.1 (C3), 119.0 (C13^AN), 109.6 (C2), 65.7 (C11^AN), 57.8 (C6). HRMS (ESP-TOF) m/z for CgHioNaO^ (MNa⁺) calculated : 205.0471; found : 205.0478. Thus, examples 3-4 and 6-10 demonstrate that a variation of esters can be formed by varying the compounds of Formula (III), with good overall yields over three steps from the starting glucono-lactone.

EXAMPLE 11 : Synthesis of 5-fhvdroxymethyl^')furan-2-carboxylic acid fHMFA^')

The procedure of example 3 is repeated using water rather than methanol as solvent (corresponding to R¹ = hydrogen). Initial experiments indicate high conversion in the final step to provide HMFA in good yields from the glucone-lactone.

EXAMPLE 12: Synthesis of 5-(hvdroxymethyl)furan-2-carboxylic acid (HMFA) (7)

Method 1; D-glucono-6-lactone (20.5 g, 115 mmol) was suspended in acetic anhydride (56 mL, 0.59 mol) together with freshly washed Amberlite® IR-120 (H) and stirred for 30 minutes at 60 °C. The resulting clear mixture was filtered and NaOAc (10.7 g, 131 mmol) was added at 60 °C, stirred overnight at 40 °C and heated to 60 °C, after 3 hours

NMR indicates >95% conversion. The reaction mixture was cooled to room temperature, filtered and everything washed twice with 25 mL toluene then concentrated, this was suspended in 25 mL toluene, filtered, washed twice with 10 mL toluene and concentrated again to yield yellow syrup of compound 1. This was dissolved in 70 mL MeOH together with AcCI (0.82 mL, 11.5 mmol) and refluxed until TLC indicated full conversion. The mixture was cooled and 0.8 M HCI (22 mL) was added to the solution, this mixture was refluxed for 30 minutes and 10 mL of H20/MeOH mixture was distilled off. The mixture was further concentrated to give a black solid that was easily soluble in MeOH, NMR indicates that this crude product is ~95 % pure 5-(hydroxymethyl)furoic acid (HMFA), 7.

*H NMR (500 MHz, MeOD) d 7.12 (d, J = 3.5 Hz, 1H, H3), 6.43 (d, J = 3.5 Hz, 1H, H4), 4.54

161.8 (Cl^c=0),

160.5 (C5), 145.5 (C2), 120.0 (C3), 110.3 (C4), 57.4 (C6^hydroxymethy')· Method 2; A crude mixture of 1 in acetic acid (40-50 % by weight) was added 5 mL (1M H2SO4) and the resulting mixture was heated to 90 °C overnight. TLC showed full conversion and after the black solution had cooled, the ^ NMR indicates a final mixture of HMFA, 7 (~15 % by weight, in 3: 17 H20/acetic acid).

EXAMPLE 13: Synthesis of Methyl 5-(chloromethyl)furan-2-carboxylate (8)

Method 1; D-glucono-6-lactone (20.06 g, 112.6 mmol) was suspended in AC2O (55 ml_, 582 mmol) then catalytic amount of I2 (23 mg, 0.09 mol%) was added and stirred for 45 minutes at 55 °C, when the solution cleared and TLC indicates full conversion. The resulting mixture was added NaOAc (11.0 g, 134 mmol) and heated to 60°C, after 3.5 hours, ^ NMR indicates >95% conversion. The reaction mixture was then concentrated, dissolved in either EtOAc or Et20, filtered and concentrated to yield yellow syrup (31.58 g), used further as is.

From this crude syrup 18.03 g (~63 mmol) was dissolved in 100 ml_ MeOH, and AcCI (10 ml_, 140 mmol) was added slowly to the mixture, through a reflux condenser, a considerable amount of heat is produced during this step. After 20 minutes TLC indicates full conversion and the reaction mixture is concentrated, and redissolved in 50 mL MeOH and stirred overnight at 22 °C. The mixture was concentrated and taken up in aqueous 37 % HCI (42 mL) and catalytic amount of H2SO4 (95 %, 20 pL) was added. The reaction mixture was heated to 50 °C for 1 hour and allowed to cool before 8 g NaCI was added to the solution. This was then poured into a separation funnel and extracted eight times by 30 mL CH2CI2, and the combined organic layers were washed with H2O, brine, dried with Na2S0₄, filtered and concentrated to dark orange oil (7.11g). This was purified by vacuum distillation to give the product 8 (4.38 g, 40 %) as yellow oil that solidifies upon storage at 4 °C and the corresponding acid (485 mg, 4.8 %) was isolated as a colorless sublimed crystalline solid on the sides of the distillation adaptor. bp 80-82 °C (1.6-I.dhq-¹ mbar), *H NMR (500 MHz, CDCI3) d 7.13 (d, ³J = 3.5 Hz, 1H, H3), 6.49 (d, 3J = 3.5 Hz, 1H, H4), 4.59 (s, 2H, H6chloromethyl), 3.90 (s, 3H, CH₃ ^ester)· ¹³C NMR (126 MHz, CDCb) d = 158.9 (Cl^c=0), 154.3 (C5), 144.9 (C2), 119.0 (C3), 111.5 (C4), 52.2 (CH₃ ^ester), 36.8 (C6^chloromethy')· HRMS (ESP-TOF) m/z for C7H7NaCI03+ (M+H+) calculated : 175.0156; found : 175.0156.

Method 2; HMMF, 2 (0.90 g, 5.76 mmol, 1.0 eq) was dissolved in 5 eq. HCI (37%, aq) and heated for 1 h at 50 °C. Afterwards, the reaction mixture was quenched with 30 ml_ Et20, washed twice with water (5 ml_), once with brine (5 ml_), dried with MgS04, filtered and concentrated. The crude product was purified by column chromatography (1 :9 acetone/toluene) to yield compound 8 as yellowish oil (0.62 g, 62 %).

*H NMR (500 MHz, CDCb) d 7.13 (d, J = 3.5 Hz, 1H), 6.49 (d, J = 3.5 Hz, 1H), 4.59 (s, 2H), 3.90 (s, 3H). ¹³C NMR (126 MHz, CDCI3) d 158.94, 154.27, 144.94, 118.96, 111.52, 52.22, 36.80. HMRS (ESP) m/z for 4+Na⁺ calculated : 196.9976; found : 196.9977. This example shows the conversion of HMMF (2) into alkylating agent 8.

EXAMPLE 14: Synthesis of Methyl 5-fbromomethyl^')furan-2-carboxylate f9~)

HMMF, 2 (2.91 g, 18.64 mmol, 1.0 eq) was dissolved in 5 eq. HBr (47%, aq) and stirred for 115 hours at room temperature. Afterwards, the reaction mixture was quenched with 10 mL H2O, extracted three times with EtOAc (30 mL). The organic phase was washed twice with water (15 mL), twice with brine (15 mL), dried with MgS0₄, filtered and concentrated. The crude product was purified by column chromatography (1 : 5 EtOAc/ Heptane) to yield compound 9 as colorless oil (3.37 g, 83 %).

*H NMR (500 MHz, CDCb) d 7.12 (d, J = 3.4 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 4.48 (s, 2H), 3.90 (s, 3H). ¹³C NMR (126 MHz, CDCb) d 158.78, 154.27, 144.77, 119.02, 111.54, 52.09, 21.92. HMRS (ESP) m/z for 5+H⁺ calculated : 218.9651, found : 218.9650; for 5+Na⁺ calculated : 240.9471, found : 240.9469.

This example shows the conversion of HMMF (2) into alkylating agent 9. EXAMPLE 15: Synthesis of 2.5-Furandicarboxylic acid ίΐq^')

Method 1 ; HMMF, 2 (220 mg, 1.41 mmol, 1.0 eq) was dissolved in solution made of H2O (15 ml) and NaOH (1.30 g, 32.43 mmol, 23.0 eq). KMnCM (512 mg, 3.24 mmol, 2.3 eq.) was added under stirring and this was continued for 30 minutes at 22 °C. The reaction mixture was filtered to remove Mn20, the flask and filtercake were washed with 10 mL H2O. Afterwards, 37 % HCI (aq.) was added to the filtrate so as to bring the pH to 1. The precipitate was separated by filtration, washed with water and dried to produce compound 10 (165 mg, 75 %).

*H NMR (500 MHz, DMSO-de) d 13.61 (br, 2H), 7.29 (s, 2H). ¹³C NMR (126 MHz, DMSO-de) d 158.88, 147.01, 118.40. HMRS (ESP) m/z for 6+H⁺ calculated : 157.0131, found : 157.0362; for 6+Na⁺ calculated : 178.9951, found : 178.9963.

Method 2; Methyl 5-(hydroxymethyl)furan-2-carboxylate, 2 (700 mg) was dissolved in 1,2-dichloroethane (4 mL), then Fe(N03)3-9H20 (362 mg, 0.2 eq.), TEMPO (140 mg, 0.2 eq.) and KCI (33 mg, 0.1 eq.) were added. The flask was sealed with a rubber septum and an O2 balloon was added. ^-NMR indicated the starting material was converted into aldehyde within one day, but the full conversion into the carboxylic acid was first obtained after 5-7 days. The mixture was concentrated and dissolved in 0.1M NaOH, the insoluble residue was removed by filtration. The filtrate was acidified using 37 % HCI (aq.) to pH¾ l. The desired products precipitated as white yellow solid with 4: 1 ratio between the mono-ester and dicarboxylic acid 10.

Entry HMMF Reaction time Yield

1 700 mg 7 days 23 %

2 5.2 g 5 days 42 %

3 540 mg 2 days n.d.^a ^a The reaction was refluxed for 2 days, only formation of the aldehyde was observed, it did not oxidize further into the carboxylic acid. This example demonstrate the oxidation of HMMF into FDCA, using both a stoichiometric and a catalytic approach.

References

• WO 2016/141148 A1

• US 9,169,227 B2

• Moreau et. al. Topics in Catalysis Vol 27, Nos. 1-4, 2004, 11-30

• Pedersen, C. Carbohydr. Res. 315, 192-197 (1999).

· Lichtenthaler, F. W., Ronninger, S. & Jarglis, Liebigs Ann. der Chemie 1989,

1153-1161 (1989).

• Elangovan, S. et al. Angew. Chemie Int. Ed. 55, 15364-15368 (2016).

• Braisted, A. C. et al., J. Am. Chem. Soc. 125, 3714-3715 (2003).

Claims

1. A method for producing a compound of Formula (I)

comprising contacting a compound of Formula (II)

with a compound of Formula (III)

H-YR¹ (III) and at least one acid,

wherein

Y is selected from the group consisting of O, NH, N R¹), and S,

R², R³ and R⁴ are an alcohol protecting group.

2. The method according to claim 1, wherein R¹ is selected from the group consisting of an optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

3. The method according to any one of claims 1-2, wherein R², R³ and R⁴ are an alcohol protecting group independently selected from the group consisting of optionally substituted C1-C10 acyl, optionally substituted C1-C10 alkoxycarbonyl, optionally substituted C1-C10 alkylsilyl, tert-butyl, optionally substituted C1-C10 alkoxythiocarbonyl, optionally substituted C1-C10 N-alkylaminocarbonyl,

methoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, borate ester, boronate ester.

4. The method according to any one of claims 1-3, wherein R², R³ and R⁴ are independently selected from optionally substituted C1-C4 acyl, optionally substituted C1-C4 alkoxycarbonyl.

5. The method according to any one of claims 1-4, wherein R², R³ and R⁴ are acetyl.

6. The method according to any one of claims 1-5, wherein H-YR¹ is solvent.

7. The method according to claim 6, wherein no further solvents are present.

8. The method according to any one of claims 1-7, wherein Y is O.

9. The method according to any one of claims 1-8, wherein R¹ is C1-C10 alkyl.

10. The method according to claim 9, wherein R¹ is C1-C3 alkyl.

11. The method according to any one of claims 1-10, wherein H-YR¹ is selected from the group consisting of methanol, ethanol and propanol.

12. The method according to claim 1 and claims 3-8, wherein H-YR¹ is H2O.

13. The method according to any one of claims 1-12, wherein he compound of Formula (I) is 5-(hydroxymethyl)furan-2-carboxylic acid (HMFA), methyl 5- (hydroxymethyl)furan-2-carboxylate (HMMF), ethyl 5-(hydroxymethyl)furan-2- carboxylate, or propyl 5-(hydroxymethyl)furan-2-carboxylate.

14. The method according to claim 13, wherein he compound of Formula (I) is methyl 5-(hydroxymethyl)furan-2-carboxylate (HMMF).

15. The method according to any one of claims 1-14, wherein the at least one acid is selected from the group consisting of Bronsted acids and Lewis acids.

16. The method according to any one of claims 1-14, wherein the at least one acid is selected from the group consisting of mineral acids and Lewis acids.

17. The method according to any one of claims 1-15, wherein the acid is selected from the group consisting of HCI, HBr, HI, HF, H3PO4, H2SO4, HNO3, H3BO3, HCIO4, TfOH, MsOH, TsOH, polyphosphoric acid, BF3-OEt2, I2, FeCb, Nafion, IR-120, and zeolites.

18. The method according to claim 17, wherein the acid is selected from the group consisting of HCI, HBr, H3PO4, H2SO4, HNO3, TfOH, BF3-OEt2, I2, FeCb.

19. The method according to claim 16, wherein the at least one acid is a mineral acid.

20. The method according to any one of claims 1-19, wherein the method is performed at a temperature in the range of 0-200 °C, such as 5-150 °C, 10-120 °C, 15-100 °C, 20-80 °C, 25-70 °C, 30-65 °C, 35-60 °C, such as preferably 40-60 °C.

21. The method according to any one of claims 1-20, wherein the compound of Formula (II) is produced by a method comprising contacting the compound of Formula (IV)

with a base, wherein

R², R³, R⁴, and R⁵ are an alcohol protecting group.

22. The method according to claim 21, wherein R², R³, R⁴ and R⁵ are an alcohol protecting group independently selected from the group consisting of optionally substituted Ci-Cio acyl, optionally substituted Ci-Cio alkoxycarbonyl, optionally substituted Ci-Cio alkylsilyl, tert-butyl, optionally substituted Ci-Cio

alkoxythiocarbonyl, optionally substituted Ci-Cio N-alkylaminocarbonyl,

methoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, borate esters, boronate esters.

23. The method according to any one of claims 21-22, wherein the base is an organic base or an inorganic base.

24. The method according to claim 23, wherein the base is selected from the group consisting of NaOAc, KOAc, LiOAc, Et3N, pyridine, collidine, TMP, DBU, CaC0₃, CeCOs, U2CO3, Na₂C0₃, K2CO3, UHCO3, NaHCOs, KHCO3, U3PO4, Na₃P0₄, K3PO4, U2HPO4, Na₂HP04, K2HPO4, CaO, CaOh , NaOH, KOH, zeolites, IR-400.

25. The method according to claim 24, wherein the base is NaOAc.

26. The method according to any one of claims 21-25, wherein the method is performed at a temperature in the range of 0-200 °C, such as 5-180 °C, 10-170

°C, 15-160 °C, 20-150 °C, 25-140 °C, 30-130 °C, 35-120 °C, 40-110 °C, 45-100 °C, 50-90 °C, 55-80 °C such as preferably 55-65 °C.

27. The method according to claim 21-26, wherein the compound of Formula (IV) is produced by a method comprising contacting the compound of Formula (V)

28. The method according to claim 27, wherein the reagent is AC2O, isopropenyl acetate, or acetyl chloride.

29. The method according to any one of claims 27-28, wherein the method is performed in neat AC2O.

30. The method according to any one of claims 27-29, wherein the method is performed at a temperature in the range of 0-200 °C, such as 5-180 °C, 10-170 °C, 15-160 °C, 20-150 °C, 25-140 °C, 30-130 °C, 35-120 °C, 40-110 °C, 45-100 °C, 50-90 °C, 55-80 °C such as 10-40 °C, 15-35 °C, such as preferably 20-30 °C.

31. The method according to any one of claims 27-30, wherein compound of Formula (V) is D-glucono-6-lactone.

32. The method according to any one of claims 1-20, wherein compound of Formula (II) is provided by performing the method of any one of claims 21-26 and any one of claims 27-31 in one pot.

33. The method according to claim 1-32, wherein the compound of Formula (I) is further converted to 2,5-furandicarboxylic acid (FDCA).