Method for producing levulinic acid and its derivatives

Abstract

The present invention relates to the field of organic synthesis, and in particular to a method for producing levulinic acid or a salt thereof, or a levulinic acid salt.

Description

[Technical field]

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for the preparation of levulinic acid or its salts, or levulinate esters (levulinates). [Background technology]

[0002] Levulinic acid (also known as 4-oxopentanoic acid) is a keto acid and therefore has two different reactive functional groups: a carbonyl functional group and a carboxyl functional group. The presence of these two groups makes levulinic acid and its derivatives versatile intermediates for the synthesis of numerous derivatives. For example, levulinic acid ketals and esters are used as high-performance solvents and dispersants for personal care formulations (anti-aging, anti-acne, skin whitening, sun protection). Levulinate esters are used as flavor additives in the food industry. Further fields of application are household and industrial cleaning agents. Industrially relevant compounds that can be produced starting from levulinic acid include, inter alia, levulinic acid ketal, 5-methyl-2-pyrrolidone, 2-methyltetrahydrofuran (MTHF), succinic acid, γ-valerolactone (GVL), 5-aminolevulinic acid, diphenolic acid (DPA) and levulinate ester. At present, the production technology and market demand for levulinic acid have not yet developed in line with previous expectations, and direct production from biomass is still under development. EP3055283A1 discloses a method for producing levulinic acid from sugar. The method described in EP3055283A1, which can be scaled up to 10,000 tons per year, is from cellulosic biomass or sugar-containing raw materials when treated with mineral acid at high temperature.

[0003] The process described in EP 3055283 A1 includes a first step of heating a first mixture comprising water and sulfuric acid to about 80 to about 160° C. to form a solution, a second step of adding a second mixture of water and sugars selected from glucose and sucrose to the heated solution over a first period of time to form a liquid reaction mixture in a reactor, where the liquid reaction mixture comprises 20% to 60% sulfuric acid, and a third step of recovering levulinic acid from the reaction mixture. This process is highly sensitive to reaction parameters such as temperature regimes that significantly alter the yield of the desired levulinic acid and several by-products. An important negative feature of this process is the formation of char and the by-product formic acid (FA). The need for separation of the formed formic acid, as well as separation and disposal of the char, are significant drawbacks of the process. Thus, there is an industry need for new processes for the production of levulinic acid that result in higher yields and require less downstream processing than prior art production processes. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] EP3055283A1 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to overcome the shortcomings of the prior art. [Means for solving the problem]

[0006] In a first aspect, the present invention relates to a method for preparing levulinic acid, a salt thereof or a levulinate ester comprising the steps of: a) providing a homogeneous or heterogeneous reaction mixture comprising: - polar protic solvents, in other words polar hydrogen bond donor solvents; and - muconic compounds, which means compounds selected from the list comprising muconic acid, muconate salts, muconic acid esters, mucono(di)lactones (in other words muconolactones or muconodilactones), either substituted or unsubstituted; and b) heating the reaction mixture provided in step a) at a temperature Ti of at least about 120° C. and at a pressure Pi greater than or equal to the autogenous pressure, thereby preparing levulinic acid, levulinate ester or a salt thereof. Effect of the Invention

[0007] The present invention offers several advantages. Levulinic acid, levulinate ester or its salts are obtained in higher yields and by means of less labor-intensive methodologies compared to the prior art. Also, by this means, the production of undesired by-products is reduced, so that levulinic acid, levulinate ester or its salts can be easily separated. By means of the present invention, only CO2 is produced as a by-product, which is easy to separate, since it separates spontaneously. It has further been found that various additives such as inorganic salts such as Na, Li, K, Mg, Ca chlorides, phosphates and sulfates do not significantly affect the high yield of levulinic acid, thereby making it possible to carry out the reaction on unpurified muconic acid, i.e. directly from the fermentation of a bio-based feedstock such as sugar. Another advantage of the present invention is that the reaction can be carried out under mild conditions, thereby not requiring the use of corrosion-resistant reactor materials. Levulinic acid, levulinate ester or its salts can all be obtained by means of a single reaction step, without the need for separation and / or post-treatment of reaction intermediates.

[0008] According to one embodiment of the invention, in step a), the mucon compound has the general formula (I): [ka] In the formula (I), the following definitions are given: - A 1 , A 2 is independently selected from the list including H, alkyl, and a cation; - R 1 , R 2 , R 3 , R 4 is independently selected from the list consisting of H, alkyl, alkenyl, carboxyl, aryl; R 2 , R 3 at least one of is H; - R 1 C-CR 2 and R 3 C-CR 4 is a double C-C bond; or - A 1 The oxygen to which it is attached is R 3 represents a direct bond linking the carbon atom at position 1 to the carbon atom at position 2, thereby forming a five-membered ring; - A 2 is selected from the list including H, alkyl, and cation; - R 1 , R 2 , R 4 is independently selected from the list including H, alkyl, alkenyl, carboxyl, aryl; - R 1 C-CR 2 is a double C-C bond, and R 3 C-CR 4 is a single C-C bond; or - A 1 , respectively A 2 is R 3 R 2 each represents a direct bond connecting an oxygen bonded to a carbon atom at the 2-position, thereby forming a fused system of two 5-membered rings; - R 1 , R 4 is independently selected from the list including H, alkyl, alkenyl, carboxyl, aryl; - R 1 C-CR 2 and R3 C-CR 4 is a single C-C bond.

[0009] According to a further embodiment of the invention, step b) comprises heating the reaction mixture at a temperature Ti of at least 160° C., more preferably at least 180° C. This embodiment has been advantageously found to provide higher yields without side reactions.

[0010] According to one embodiment of the invention, in step a), the polar protic solvent is water. The advantage of this embodiment is that the reaction is more environmentally friendly while providing high yields.

[0011] According to one embodiment of the present invention, in step a), the polar protic solvent is an alcohol. The advantage of this embodiment is that the reaction directly provides the value-added levulinate ester.

[0012] According to one embodiment of the invention, the reaction mixture further comprises a basic catalyst, i.e. a base that acts as a catalyst for the reaction. The advantage of this embodiment is that higher yields can be achieved and lower temperatures can be used compared to reactions without such a basic catalyst.

[0013] According to one embodiment of the invention, the basic catalyst comprises one or more sp3 hybridized nitrogen atoms, in other words the catalyst comprises a nitrogen atom with sp3 hybridization.

[0014] An advantage of this embodiment is that higher yields can be achieved and the base can be easily separated from the levulinate ester product by extraction means.

[0015] According to an embodiment of the present invention, the basic catalyst is selected from the list comprising diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene.

[0016] The advantage of this embodiment is that these amines give the best results. According to one embodiment of the invention, step a) comprises providing the mucone compound in the cis,cis-, cis,trans- or trans,cis-configuration, preferably the cis,cis-configuration.

[0017] The advantage of starting with cis,cis-muconic acid is that it is the isomer that can be obtained directly by fermentation.

[0018] According to one embodiment of the invention, step b) comprises heating the reaction mixture in a non-oxidizing atmosphere that does not result in oxidation of the reactants and / or products, such as N2, Ar, etc. The advantage of this embodiment is that side reactions that adversely affect obtaining the product are reduced.

[0019] According to one embodiment of the invention, steps a) and b) are carried out successively without isolating any intermediates, in other words the process according to the invention is a one-pot reaction. [Brief description of the drawings]

[0020] With particular reference now to the drawings, it is emphasized that the details shown are illustrative and are for the purpose of illustrative discussion of different embodiments of the present invention only. They are presented as a basis for providing what is believed to be the most useful and facile explanation of the principles and conceptual aspects of the present invention. In this regard, no structural details of the present invention are described in more detail than is necessary for a fundamental understanding of the present invention. The description using the drawings is provided to make clear to those skilled in the art how some aspects of the present invention can be embodied in practice.

[0021] [Figure 1] FIG. 1, also referred to as FIG. 1, shows the results of a sampling experiment for the synthesis of levulinic acid from cis,cis-muconic acid (see Example 9). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention will now be described further. In the following sections, different aspects of the present invention are defined in more detail. Each aspect so defined can be combined with any other aspect, unless it is clearly indicated that it does not apply. In particular, any feature that is indicated as being preferred or advantageous can be combined with any other feature that is indicated as being preferred or advantageous. When describing the compounds of the present invention, the terms used should be interpreted according to the following definitions, unless the context indicates otherwise.

[0023] As used herein, when referring to a measurable value such as a parameter, amount, duration, and the like, the term "about" or "approximately" is meant to encompass within + / - 10% of the particular value, preferably within + / - 5%, more preferably within + / - 1%, and even more preferably within + / - 0.1%, and such variations from the particular value, as appropriate for practice in the disclosed invention. It is to be understood that the value to which the modifier "about" or "approximately" is recited is itself also the disclosed, specific and preferred.

[0024] In a first aspect, the present invention provides a method for preparing levulinic acid, or a salt thereof, or a levulinate ester, comprising the steps of: a) providing a reaction mixture comprising: - polar protic solvents; and - a muconic compound selected from the list comprising muconic acid, muconates, muconic acid esters, mucono(di)lactone; and b) heating the reaction mixture provided in step a) at a temperature Ti of at least about 120° C. and at a pressure Pi≧autogenous pressure, thereby preparing levulinic acid or a salt thereof, or a levulinate ester. According to the present invention, the term "levulinic acid, levulinate ester or salt" refers to a compound having the formula (II): [ka] During the ceremony - B is selected from the group comprising H, alkyl, inorganic cations, organic cations; - R 5 , R 6 is selected from the group including, but not limited to, H, alkyl, alkenyl, carboxyl, aryl.

[0025] In particular, levulinic acid is a carboxylic acid in which B is H and R 5 and R 6 corresponds to the compound of formula (II) in which B is H, levulinate ester (also called simply levulinate or levulinic acid ester in the context of the present invention) corresponds to the compound of formula (II) in which B is alkyl, and levulinate salt corresponds to the compound of formula (II) in which B is either an organic or inorganic cation. Levulinic acid, levulinate ester and levulinic acid salt obtainable according to the present invention can also be substituted (R 5 and R 6 (see base).

[0026] The term “alkyl,” by itself or as part of another substituent, refers to a group of the formula C x H 2x+1(wherein x is a number equal to or greater than 1) refers to a fully saturated hydrocarbon. Generally, the alkyl groups of the present invention contain from 1 to 20 carbon atoms. The alkyl groups may be linear or branched and may be substituted as provided herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the designated group may contain. Thus, for example, C 1-4 Alkyl means alkyl of 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and its isomers. C1-C6 alkyl includes all linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3- or 4-methylcyclopentyl, cyclopentylmethylene and cyclohexyl. The term "optionally substituted alkyl" refers to an alkyl group that is optionally substituted at any available point of attachment with one or more substituents (e.g., 1 to 4 substituents, e.g., 1, 2, 3, or 4 substituents, or 1 to 2 substituents). Non-limiting examples of such substituents include halo, hydroxyl, carbonyl, nitro, amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl ester, carbamate, thioamide, urea, sulfonamide, and the like.

[0027] The term "alkenyl" as used herein, unless otherwise specified, refers to a straight-chain, cyclic, or branched-chain hydrocarbon group containing at least one carbon-carbon double bond. In general, the alkenyl group of the present invention contains 2 to 20 carbon atoms. Examples of alkenyl groups include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E-, Z,Z-hexadienyl, and the like. Optionally substituted alkenyl refers to an alkenyl that may have one or more substituents (e.g., 1, 2, 3, or 4) selected from those defined above for substituted alkyl. The term "alkynyl" as used herein, unless otherwise specified, refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Optionally substituted alkynyl refers to alkynyl that may bear one or more substituents (e.g., 1, 2, 3, or 4) selected from those defined above for substituted alkyl.

[0028] The term "cycloalkyl" by itself or as part of another substituent means a cyclic alkyl group, i.e., a monovalent, saturated or unsaturated hydrocarbyl group having one, two or three ring structures. Cycloalkyl includes all saturated or partially saturated (containing one or two double bonds) hydrocarbon groups containing one to three rings, including monocyclic, bicyclic or polycyclic alkyl groups. Cycloalkyl groups may contain three or more carbon atoms in the ring, and generally, according to the present invention, contain 3 to 15 atoms. The further rings of polycyclic cycloalkyls may be fused, bridged and / or linked through one or more spiro atoms. Cycloalkyl groups may also be considered to be a subset of homocyclic rings, discussed below.

[0029] Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, and cyclodecyl, with cyclopropyl being particularly preferred. "Optionally substituted cycloalkyl" refers to cycloalkyl that may have one or more substituents (e.g., 1 to 3 substituents, e.g., 1, 2, 3, or 4 substituents) selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group (hereinafter also referred to as "cycloalkylene"), this is intended to mean a cyclic group as defined herein having two single bonds as points of attachment to other groups. Cycloalkylene groups of the present invention preferably contain the same number of carbon atoms as their cycloalkyl radical counterparts. When the defined alkyl groups are divalent, i.e., have two single bonds for attachment to two other groups, they are referred to as "alkylene" groups. Non-limiting examples of alkylene groups include methylene, ethylene, trimethylene, propylene glycol, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene and hexamethylene. Similarly, when an alkenyl group as defined above and an alkynyl group as defined above are divalent radicals having single bonds for attachment to two other groups, respectively, they are referred to as "alkenylene" and "alkynylene", respectively.

[0030] In general, alkylene groups of the present invention preferably contain the same number of carbon atoms as their alkyl counterparts. When an alkylene or cycloalkylene biradical is present, the attachment to the molecular structure it forms part of may be via a common carbon atom or different carbon atoms, preferably a common carbon atom. Applying the asterisk nomenclature of the present invention, a C3 alkylene group is, for example: * -CH2CH2- * , * -CH(-CH2CH3)- * or * -CH2CH(-CH3)- *Similarly, a C3 cycloalkylene group can be: [ka] When a cycloalkylene group is present, it is preferably a C3-C6 cycloalkylene group, more preferably a C3 cycloalkylene (i.e., a cyclopropylene group), where its attachment to the structure it forms part of is via a common carbon atom. The cycloalkylene and alkylene biradicals in the compounds of the invention may be substituted, but are preferably unsubstituted.

[0031] The term "aryl" as used herein refers to a polyunsaturated aromatic hydrocarbyl group, typically containing 6 to 10 atoms, having a single ring (i.e., phenyl) or multiple aromatic rings fused or covalently bonded together (e.g., naphthalene or anthracene), in which at least one ring is aromatic. The aromatic ring may optionally contain 1 to 3 additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Non-limiting examples of aryl are phenyl, biphenylyl, 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or 2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1-, 2-, 3-, 4-, or 5-acenaphthylenyl, 3-, 4-, or 5-acenaphthenyl, 1-, 2- ... Aryl groups include 1-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1-, 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, dibenzo[a,d]cycloheptenyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. The aryl ring may be optionally substituted by one or more substituents.

[0032] "Optionally substituted aryl" refers to an aryl that may have one or more substituents (e.g., 1 to 5 substituents, e.g., 1, 2, 3, or 4) at any available point of attachment. Non-limiting examples of such substituents include halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO2-NH2, aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamido, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO2R a , alkylthio, carboxyl, etc.; R a is alkyl or cycloalkyl. When a carbon atom in an aryl group is replaced with a heteroatom, the resulting ring is referred to herein as a heteroaryl ring.

[0033] "Optionally substituted heteroaryl" refers to a heteroaryl optionally bearing one or more substituents (e.g., 1 to 4 substituents, e.g., 1, 2, 3 or 4) selected from those defined above for substituted aryl. As used herein, the term "oxo" refers to the group =O. As used herein, the term "alkoxy" or "alkyloxy" refers to a group of the formula -OR b (In the formula, R b Alkoxy refers to a radical having a C1-C 10 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy. Non-limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. When the oxygen atom in an alkoxy group is replaced with sulfur, the resulting radical is called thioalkoxy.

[0034] The term "aryloxy" as used herein refers to the group -O-aryl, where aryl is as defined above. The term "arylcarbonyl" or "aroyl" as used herein refers to the group -C(O)-aryl, where aryl is as defined above. The terms "carboxy" or "carboxyl" or "hydroxycarbonyl", by themselves or as part of another substituent, refer to a -CO2H group. Thus, a carboxyalkyl is an alkyl group, as defined above, having at least one substituent that is -CO2H. The term "alkoxycarbonyl", by itself or as part of another substituent, refers to a carboxy group linked to an alkyl radical, i.e., -C(=O)OR e where R e is as defined above for alkyl. The term "alkylcarbonyloxy" by itself or as part of another substituent means -OC(=O)R e where R e is as defined above for alkyl.

[0035] The term "alkoxy" by itself or as part of another substituent refers to a group consisting of an oxygen atom bonded to an optionally substituted straight or branched alkyl, cycloalkyl, aralkyl, or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexanoxy, and the like. The term "halo" or "halogen" as a group or part of a group is a generic term for fluoro, chloro, bromo, or iodo. Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the indicated atom in the expression using "substituted" are replaced with a selection from the indicated group, provided that the normal valence of the indicated atom is not exceeded and the replacement results in a chemically stable compound.

[0036] The present invention comprises a first step a) of obtaining a reaction mixture comprising a polar protic solvent and a mucon compound.

[0037] In the present invention, the meaning of the term "reaction mixture" refers to a homogeneous or heterogeneous mixture, which may be modified and adapted to be heated under pressure, for example in a pressurized reactor. For example, the reaction mixture according to the present invention is a solution and / or suspension of one or more compounds provided to be heated under pressure according to the present invention. Thus, according to the present invention, the muconic compound is completely dissolved, partially dissolved or not dissolved in the polar protic solvent (thereby providing a suspension). In the context of the present invention, it is to be understood that besides the polar protic solvent, the reaction mixture may contain one or more other solvents that are not protic. For example, the reaction mixture may contain a solution of methanol and acetone or water and acetone in various proportions.

[0038] In a particular embodiment according to the present invention, the reaction mixture further comprises one or more additives. Thus, in order to fine-tune the reaction conditions and, for example, improve the yield, one or more additives can be added to the reaction mixture. It has been found that the method according to the present invention is compatible with the use of either acidic or basic additives.

[0039] The term "polar protic solvent" refers to one or more liquid compounds that are both polar and protic. Liquid compounds that provide both polar and protic properties include, for example, those that contain one or more highly electronegative atoms such as O, N, F bonded to a hydrogen atom. Examples of polar protic solvents include, but are not limited to, acetic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, formic acid, and water.

[0040] According to one embodiment of the present invention, in step a), the polar protic solvent is selected from the list comprising water, polar protic organic solvent. Examples of polar protic organic solvents are, but are not limited to, acetic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, formic acid. The term "organic solvent" refers to a solvent that is carbon-based, in other words, that contains at least one carbon atom.

[0041] According to one embodiment of the invention, in step a), the polar protic solvent is selected from the list comprising water, alkyl alcohols, such as methanol, ethanol, and mixtures thereof. According to one embodiment of the invention, in step a), the polar protic solvent is water. The use of water as polar protic solvent is advantageous for several reasons, in particular water is a non-toxic, non-flammable, readily available and very cheap solvent, and it does not pose any inconveniences such as its waste disposal, since it can be separated from the obtained levulinic compound simply by evaporation. Moreover, its stability and non-flammability make water a better solvent to work with overall, especially in industrial environments.

[0042] According to the present invention, water can also be used without the addition of any acid and / or base. This further simplifies the implementation of the method according to the present invention, avoiding the use of corrosive bases and acids. Thus, according to a further embodiment, the method of the present invention can be carried out in the absence of acids and / or bases dissolved in water. The use of water as a polar protic solvent allows the production of levulinic acid from various substrates and provides high yields. In particular, the use of water as a polar protic solvent provides levulinic acid from all of cis,cis-muconic acid, cis,trans-muconic acid, muconolactone and muconodilactone (muconic acid dilactone) without the use of additives, such as bases or acids. This allows a flexible synthesis strategy adapted to work with various interrelated substrates.

[0043] Thus, according to one embodiment of the present invention, in step a), water is not provided to contain any basic or acid additives, so that the reaction mixture is not provided with an adjusted pH different from that of the reaction mixture provided by the muconic compound or compounds alone. According to a further particular embodiment of the present invention, in step a), the reaction mixture consists of water and one or more muconic compounds. In yet a further particular embodiment of the present invention, in step a), the reaction mixture consists of a polar protic organic solvent and one or more muconic compounds. In yet a further particular embodiment of the present invention, in step a), the reaction mixture consists of an alkyl alcohol and one or more muconic compounds.

[0044] When levulinic acid is to be obtained from trans,trans-muconic acid, water can also be used as a solvent. The use of an additive, for example an acid additive (such as HCl), or increasing the reaction temperature, for example to 250° C., has been found to be beneficial to this process.

[0045] According to one embodiment of the present invention, in step a), the polar protic solvent is an alkyl alcohol. The advantage of this embodiment is that levulinic acid alkyl esters, in other words alkyl levulinates, can be obtained in a one-pot approach without the need to alkylate the obtained levulinic acid in a subsequent step, thereby saving synthetic resources. According to yet a further embodiment, the polar protic solvent is C 1~4 It is an alkyl alcohol, more particularly selected from the group comprising methanol, ethanol, isopropanol, propanol and butanol. According to yet a further embodiment of the invention, in step a), the polar protic solvent is methanol.

[0046] According to the present invention, the term "muconic compounds" means unsaturated 1,6-dicarboxylic compounds or their (di)lactones, such as muconic acid, muconate salts, Reference is made to muconic acid esters (also known as muconates) having either the cis,cis-, trans,trans-, cis,trans- and trans,cis-configurations, muconolactone or muconodilactone. Muconic compounds can be obtained by means of state-of-the-art methodologies such as oxidation of catechol or fermentation of carbohydrates.

[0047] According to one embodiment of the invention, in step a), the mucon compound is of general formula (I): [ka]

[0048] In general formula (I), the wavy bond indicates that the atoms involved in the bond may be in the cis,cis-, trans,trans-, cis,trans- or trans,cis-configuration. By means of the cis,cis-, trans,trans-, cis,trans- or trans,cis-configuration the following are mentioned (exemplified, without limitation, by unsubstituted muconic acid): [ka]

[0049] According to one embodiment of the invention, step a) comprises providing a muconic compound in the cis,cis-, cis,trans- or trans,cis-configuration, preferably the cis,cis-configuration. The cis,cis-configuration is preferred as these isomers are more readily available. For example, cis,cis-muconic acid isomers can be obtained by fermentation of sugars, which makes the cis,cis-isomer more accessible. According to a particular embodiment of the invention, step a) comprises providing muconic acid, an ester or a salt thereof in the cis,cis-, cis,trans- or trans,cis-configuration, preferably the cis,cis-configuration.

[0050] By means of the method according to the invention, R 1 , R 2 , R 3 and R 4 A variety of substituents at the positions are well tolerated, allowing for convenient synthetic routes to substituted levulinic acids, their esters and salts.

[0051] Furthermore, in the general formula (I), R 1 C-CR 2 and R 3 C-CR 4 The C-C bond in can be either a single or a double bond. This is represented in general formula (I) by the use of a single partial dotted bond.

[0052] Thus, the above general formula (I) represents the stereoisomers (cis,cis-, cis,trans-, etc.) and structural isomers ((di)lactones) of muconic acid, as well as its esters and salts. In particular, various group formulas are encompassed by general formula (I).

[0053] General formula (I) can be defined as follows: - A 1 , A 2 is independently selected from the list including H, alkyl, and a cation; - R 1 , R 2 , R 3 , R 4is independently selected from the list consisting of H, alkyl, alkenyl, carboxyl, aryl; R 2 , R 3 at least one of is H; - R 1 C-CR 2 and R 3 C-CR 4 is a double C-C bond; Thereby forming the base formula (IA); [ka] The group (IA) represents cis,cis-, cis,trans- or trans,cis-, trans,trans-muconic acid, esters and salts thereof. The compounds referred to herein are 1 , R 2 , R 3 and R 4 R 2 , R 3 Various substituents may further be provided, where at least one of R is H. The compounds referred to herein may also be provided unsubstituted (R 1 = R 2 = R 3 = R 4 = H). According to a particular embodiment of the invention, the mucon compound is of formula (IA):

[0054] Otherwise, general formula (I) is defined as follows: - A 1 The oxygen to which it is attached is R 3 represents a direct bond linking the carbon atom at position 1 to the carbon atom at position 2, thereby forming a five-membered ring; - A 2 is selected from the list including H, alkyl, and cation; - R 1 , R 2 and R 4 is independently selected from the list including H, alkyl, alkenyl, carboxyl, aryl; - R 1 C-CR2 is a double C-C bond, and R 3 C-CR 4 is a single C-C bond; Thereby, we construct the base formula (IB); [ka]

[0055] Therefore, the formula (IB) is R 1 , R 2 and / or R 4 It is substituted at one of the positions or is unsubstituted (R 1 = R 2 = R 4 = H), its esters and salts. 1 , R 2 and R 4 may vary. According to a particular embodiment of the invention, the muconic compound is of the formula (IB). In other words, according to a particular embodiment of the invention, the muconic compound is the monolactone of muconic acid, or an ester or salt thereof.

[0056] Otherwise, general formula (I) is defined as follows: - A 1 , respectively A 2 is R 3 R 2 each represents a direct bond connecting an oxygen bonded to a carbon atom at the 2nd position, thereby forming a fused system of two 5-membered rings; - R 1 , R 4 is independently selected from the list including H, alkyl, alkenyl, carboxyl, aryl; - R 1 C-CR 2 and R 3 C-CR 4 is a single C-C bond; Thereby, it constitutes the base formula (IC); [ka]

[0057] Therefore, the formula (IC) is R 1 rank and / or R 4 It may be substituted at any one of the positions or unsubstituted (R 1 = R 4 = H). When unsubstituted, the group (IC) represents muconodilactone. According to certain embodiments of the invention, the muconic compound is muconodilactone.

[0058] The present invention further comprises the steps of: b) heating the reaction mixture provided in step a) at a temperature Ti of at least about 120° C. and at a pressure Pi≧autogenic pressure, thereby preparing levulinic acid or its salts or levulinates. According to this process, the reaction mixture provided in step a) comprising a polar protic solvent and a muconic compound according to formula (I) is heated at a temperature of at least 120° C. under a pressure that is at least the autogenic pressure. It should be understood that the autogenic pressure depends on the temperature of the reaction mixture, the solvent and the headspace (and therefore the reactor design). For example, the theoretical pressure of water is 2 bar at 120° C., 10 bar at 180° C. and 16 bar at 200° C.

[0059] According to the present invention, the term "autogenic pressure" or "autogenous pressure" refers to the pressure that is self-generated in a closed vessel, which is required to prevent polar protic solvents from boiling.

[0060] According to a further embodiment of the invention, step b) comprises heating the reaction mixture at a temperature Ti of at least 140° C., preferably at least 160° C., more preferably at least 180° C. It has been found that higher temperatures are beneficial, in particular higher yields can be obtained. Good yields can be obtained already at temperatures of at least 160° C. At temperatures of 180° C. or higher, quantitative yields are obtained.

[0061] According to the present invention, the term "alkyl alcohol" refers to an alcohol of the general formula R(OH)n, where R is alkyl and n corresponds to the number of hydroxyl groups, e.g., when n=2, the alkyl alcohol is a diol, when n=3, the alkyl alcohol is a triol, etc.

[0062] According to one embodiment of the present invention, the polar protic solvent in step a) comprises an additive selected from the list comprising acids and bases. Possible acids that can be used as additives according to the present invention can be organic acids, such as formic acid, acetic acid, or propionic acid, or mineral acids, such as HCl or H2SO4. Here, "mineral acids" refers to acids derived from one or more inorganic compounds, such as hydrochloric acid, HBr, H2SO4, H3PO4, etc. Furthermore, possible bases that can be used as additives according to the present invention include metal hydroxides, such as NaOH or KOH. By the term "metal hydroxide" we refer to bases that comprise at least one hydroxide anion and a metal cation, such as NaOH, KOH, LiOH, Ca(OH)2, etc.

[0063] It has been found that the use of an acid, preferably a mineral acid, and a base, preferably a metal hydroxide, can be beneficial to provide higher yields, depending on the substrate used.The use of either an acid or a base additive is not required by the present invention.In other words, it is clear that levulinic acid, its salt or ester can be obtained according to the present invention without the presence of any acid or base.

[0064] According to one embodiment of the present invention, the reaction mixture further comprises a basic catalyst. According to the present invention, the term "basic catalyst" refers to a base provided to catalyze the reaction. Examples of basic catalysts according to the present invention are carboxylate salts such as, but not limited to, sodium acetate, ammonium acetate, metal hydroxides such as, but not limited to, aluminum hydroxide, compounds containing sp3 nitrogen such as, but not limited to, ammonia, and compounds containing sp2 hybridized nitrogen atoms such as, but not limited to, pyridine, etc. According to a preferred embodiment of the present invention, the basic catalyst comprises at least one sp3 hybridized nitrogen atom.

[0065] According to an embodiment of the present invention, the basic catalyst is selected from the list including diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene. It has been found that the basic catalyst of the present invention can provide the highest yield.

[0066] According to one embodiment of the invention, in step a), the mucon compound is of formula (IA), 1 and A 2 is H, and the additive is a mineral acid, preferably in a concentration of at least 1 equivalent, preferably 2 equivalents, preferably 5 equivalents, preferably 10 equivalents, or The additive is preferably a metal hydroxide in a concentration ranging from about 0.1 equivalent to about 1.5 equivalents, preferably 1 equivalent.

[0067] According to one embodiment of the invention, in step a), the mucon compound is of formula (IA), 1 and A 2 is H and the polar protic solvent is an alkyl alcohol.

[0068] According to one embodiment of the invention, step b) comprises heating the reaction mixture in a non-oxidizing atmosphere. According to the invention, by the term "non-oxidizing atmosphere" it is meant an atmosphere comprising one or more gases provided so as not to oxidize any one of the reagents, products or intermediates in the method according to the invention.

[0069] According to one embodiment of the invention, step b) comprises heating the reaction mixture in an atmosphere of a gas selected from the list comprising H2, N2, CO and CO2. It has been found to be advantageous to carry out the reaction in one of these gases, or in a mixture thereof.

[0070] According to one embodiment of the invention, steps a) and b) are carried out consecutively without isolating any intermediates, which has the advantage of allowing a one-pot reaction that saves both time and synthetic steps.

[0071] Experimental Method General Procedure A: A 4 mL glass vial was charged with a magnetic stir bar, substrate for the experiment, additives (if required) and 3 mL of the appropriate solvent or solvent mixture. The vial was properly closed with the correct cap and septum, and the septum was pierced with a syringe needle. The vial was placed in a home-made heating block in a 4596 Parr reactor (volume 25 mL) and the reactor was properly closed. The reactor was flushed with the appropriate gas (3 x 10 bar) and then pressurized with the reported pressure of this gas. The reactor was heated to the indicated reaction temperature.

[0072] The reactor was maintained at this temperature for the indicated reaction time and then cooled in an ice bath. The gas was released and the reactor was opened. After opening the reactor, a weighed amount of internal standard was added to the crude reaction mixture along with acetone until the glass vial was full. After thorough stirring, the mixture was placed in a pear-shaped flask and the glass vial was rinsed with water (about 1 mL) and acetone (about 1 mL). If the reaction took place in a non-aqueous solvent, the vial was instead rinsed with acetone (about 1 mL x 2). About half of the combined mixture was taken and evaporated. (If the reaction took place in a non-aqueous solvent, the entire mixture was evaporated and the evaporation was performed at a pressure above 60 mbar.) The residue was dissolved in an appropriate deuterated solvent and analyzed by NMR.

[0073] General Procedure B: A homemade PTFE liner was filled with the substrate for the experiment, additives (if required) and 9 mL of the appropriate solvent or solvent mixture. The insert was placed in a 4596 Parr reactor (volume 25 mL) equipped with a mechanical stirrer and the reactor was properly closed. The reactor was flushed with the appropriate gas (3×10 bar) and then pressurized to the reported pressure of this gas. The reactor was heated to the indicated reaction temperature.

[0074] The reactor was maintained at this temperature for the indicated reaction time and then cooled in an ice bath. The gas was released and the reactor was opened. After opening the reactor, a weighed amount of the internal standard was added to the crude reaction mixture along with acetone until the insert was full. After thorough stirring, the mixture was placed in a pear flask and the vial was rinsed with water (~1 mL) and acetone (~1 mL). Approximately half of the combined mixture was taken and evaporated. The residue was dissolved in an appropriate deuterated solvent and analyzed by NMR.

[0075] General Procedure C: A 4 mL glass vial was charged with a magnetic stir bar, substrate for the experiment, additives (if required) and 3 mL of the appropriate solvent or solvent mixture. The vial was properly closed with the correct cap and septum, and the septum was pierced with a syringe needle. The vial was placed in a home-made heating block in a 4651 Parr reactor (300 mL capacity) and the reactor was properly closed. The reactor was flushed with the appropriate gas (3×10 bar) and then pressurized with the reported pressure of this gas. The reactor was heated to the indicated reaction temperature for 1 h. The reactor was maintained at this temperature for the indicated reaction time and then cooled (until 180° C. was reached in air, then to RT in an ice bath).

[0076] The gas was released and the reactor was opened. Unless otherwise stated, after opening the reactor, a weighed amount of the internal standard was added to the crude reaction mixture along with acetone until the glass vial was full. After thorough stirring, the mixture was placed in a pear-shaped flask and the glass vial was rinsed with water (~1 mL) and acetone (~1 mL). If the reaction occurred in a non-aqueous solvent, the vial was instead rinsed with acetone (~1 mL x 2). Approximately half of the combined mixture was taken and evaporated. (If the reaction occurred in a non-aqueous solvent, the entire mixture was evaporated and the evaporation was performed at a pressure above 60 mbar.) The residue was dissolved in an appropriate deuterated solvent and analyzed by NMR. EXAMPLES

[0077] Example 1: Temperature screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure A using cis,cis-muconic acid (43 mg, 0.3 mmol) and water (3 mL) under initial N2 pressure of 50 bar for 3 h. [ka] 1 The 1 H NMR yields (dimethylsulfone or dimethylmalonic acid internal standard) are shown in the table below. [Table 1] a1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR. b Reaction under 90 bar N2 pressure, impurities are 1 It was visible in the 1 H NMR spectrum. c Experiments with "bis" in the experiment number refer to the same number of experimental replicates performed with different internal standards. Similar yields were obtained as in the original experiment.

[0078] Example 2: Pressure screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure B using cis,cis-muconic acid (128 mg, 0.9 mmol) and water (9 mL) at 180° C. for 3 h under the indicated N 2 pressure. 1 The 1 H NMR yields (dimethylsulfone internal standard) are shown in the table below. [ka] [Table 2] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0079] Example 3: Synthesis of levulinic acid from cis,cis-muconic acid under autogenous pressure [Experiment No. 21] A 10 mL glass vial equipped with a magnetic stir bar was charged with cis,cis-muconic acid (43 mg, 0.3 mmol) and water (3 mL). The vial was sealed with a crimp cap and metal screw cap and placed in a preheated oil bath at 180 °C for 3 h. After cooling to room temperature, the vial was opened and a weighed amount of internal standard (dimethylsulfone) was added to the reaction mixture along with acetone (~1 mL). Once all solids were dissolved, the mixture was transferred to a pear-shaped flask and the vial was washed with water (~1 mL) and acetone (~1 mL). Approximately 3 mL of the mixture was then evaporated and the residue was analyzed by quantitative NMR. Muconolactone (2,5-dihydro-5-oxo-2-furanacetic acid, 21% 1 H NMR yield) and muconic acid dilactone (tetrahydrofuro[3,2-b]furan-2,5-dione, 5% 1 1 H NMR yield) and levulinic acid 83% 1 1 H NMR yield. 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0080] Example 4: Atmospheric screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure C with cis,cis-muconic acid (43 mg, 0.3 mmol) and water (3 mL) at 180° C. for 3 h under 15 bar pressure of the indicated gas. 1 H NMR yields (dimethylsulfone internal standard) are shown in the table below. (Each experiment was performed three times and the average yields are reported with their standard deviations.) [ka] [Table 3] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR. b A brown reaction mixture was obtained.

[0081] Example 5: Concentration screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure C using cis,cis-muconic acid and water (2-3 mL) at 180° C. under 15 bar N2 pressure for 3 h. 1 The 1 H NMR yields (dimethylsulfone internal standard) are shown in the table below. [ka] [Table 4] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0082] Example 6: Additive screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure C using cis,cis-muconic acid (43 mg, 0.3 mmol), the indicated additive (0.6 mmol, 2 equiv.) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. 1 The 1 H NMR yields (dimethylsulfone internal standard) are shown in the table below. [ka] [Table 5] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR. b A significant amount of char was formed. c Runs with "bis" in the number refer to duplicates of the run with the same run number after recalibration of the reactor temperature controller. Similar yields were obtained as in the original run.

[0083] Example 7: Acid concentration screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to general procedure C using cis,cis-muconic acid (43 mg, 0.3 mmol), the indicated equivalents of HCl and water (3 mL) at 180° C. for 3 h under 15 bar N2 pressure. 1 The H NMR yields (dimethylsulfone internal standard) are shown in the table below. To measure the pH at the corresponding concentrations of HCl and cis,cis-muconic acid, cis,cis-muconic acid (1.0 mmol) and water (10 mL) were added to a 20 mL glass vial along with the equivalent amount of HCl indicated. After thorough mixing, the mixture was refluxed with a heat gun until all contents were completely dissolved. (If this resulted in significant solvent loss, additional water was added to the mixture until the solution was approximately 10 mL in volume.) The pH of the solution was then measured at RT. [ka] [Table 6] aMeasured at room temperature. b 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR. c Runs with "bis" in the number refer to duplicates of the run with the same run number after recalibration of the reactor temperature controller. Similar yields were obtained as in the original run.

[0084] Example 8: Base concentration screening for the synthesis of levulinic acid from cis,cis-muconic acid These experiments were carried out according to a modified general procedure C using cis,cis-muconic acid (43 mg, 0.3 mmol), the indicated equivalents of NaOH and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Work-up was performed by addition of the internal standard, acetone and concentrated HCl to acidify the solution. After centrifugation, approximately half of the mixture was evaporated, dissolved in DMSO-d6, filtered as necessary and analyzed by NMR. 1The H NMR yields (dimethylsulfone internal standard) are shown in the table below. To measure the pH at the corresponding concentrations of NaOH and cis,cis-muconic acid, cis,cis-muconic acid (1.0 mmol) and water (10 mL) were added to a 20 mL glass vial along with the indicated equivalent amount of NaOH. After thorough mixing, the mixture was refluxed with a heat gun until all contents were completely dissolved. (If this resulted in significant solvent loss, additional water was added to the mixture until the solution was approximately 10 mL in volume.) The pH of the solution was then measured at RT. [ka] [Table 7] aMeasured at room temperature. b 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR. c Runs with "bis" in the number refer to duplicates of the run with the same run number after recalibration of the reactor temperature controller. Similar yields were obtained as in the original run.

[0085] Example 9: Sampling experiment for the synthesis of levulinic acid from cis,cis-muconic acid [Experiment No. 60] A glass liner was charged with a magnetic stir bar, cis,cis-muconic acid (2.13 g, 15.0 mmol) and water (150 mL). The liner was placed in a 4651 Parr reactor equipped with a dip tube and sampling valve and the reactor was properly closed. The reactor was flushed with N2 (3 x 10 bar) and then pressurized with N2 (15 bar). The reactor was heated to reaction temperature for 1 h and samples (approximately 2.4 mL) were taken every 15 min. Each sample was degassed by sonication for a few seconds. An accurately measured volume of the sample was then mixed with an accurately measured volume of a stock solution of the internal standard (dimethyl sulfone) in acetone. The mixture was evaporated and analyzed using NMR. The solubility of all products present in the sample was 100%. 1 H NMR yields were normalized to 100% mass balance and plotted in Figure 1.

[0086] As shown in Figure 1, within the first 30 min, most of the cis,cis-muconic acid had already isomerized to cis,trans-muconic acid. Levulinic acid was detected after 60 min of heating. Muconolactone was formed before the appearance of levulinic acid. A small amount of muconodilactone was also present after 60 min, which increased after longer reaction times and then disappeared. The yield of levulinic acid increased steadily throughout the reaction time, reaching a maximum 255 min (4 h 15 min) after the start of heating. This demonstrates that after the reactor reached its set temperature in 1 h, it takes 3 h 15 min to reach full conversion.

[0087] Example 10: Synthesis of levulinic acid from cis,cis-muconic acid [Experiment No. 61] A 20 mL glass vial was charged with a magnetic stir bar, cis,cis-muconic acid (213 mg, 1.50 mmol) and water (15 mL). The vial was properly closed with the correct cap and septum, and the septum was pierced with a syringe needle. The vial was placed in a home-made heating block in a 4651 Parr reactor (300 mL capacity) and the reactor was properly closed. The reactor was flushed with nitrogen (3×10 bar) and then pressurized with nitrogen (15 bar). The reactor was heated to 180° C. in 1 h and maintained at this temperature for 3 h. The reactor was then cooled in an ice bath. After venting the gases and opening the reactor, the solvent was evaporated under reduced pressure to give levulinic acid as a tan oil in 97% (169 mg, 1.45 mmol) yield.

[0088] Example 10bis: Synthesis of levulinic acid from cis,cis-muconic acid with an improved separation procedure [Experiment no. 61bis] The synthesis was carried out according to Example 10, after releasing the gas and opening the reactor, the mixture was acidified with aqueous HCl (pH <2) and continuously extracted with ethyl acetate for 24 h. The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give levulinic acid as a light brown oil in quantitative yield (178 mg, 1.53 mmol).

[0089] Example 11: Synthesis of levulinic acid from cis,cis-muconic acid monomethyl ester [(2Z,4Z)-6-methoxy-6-oxohexa-2,4-dienoic acid] [Experiment No. 62] (2Z,4Z)-6-Methoxy-6-oxohexa-2,4-dienoic acid was synthesized according to literature procedures (see Jastrzebski, Robin, et al., 2015). The experiment was carried out according to general procedure C using (2Z,4Z)-6-methoxy-6-oxohexa-2,4-dienoic acid (47 mg, 0.3 mmol) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Levulinic acid was prepared by 1 The 1 H NMR yield was 95%.

[0090] Example 12: Synthesis of levulinic acid from cis,trans-muconic acid [Experiment No. 63] Cis,trans-muconic acid was synthesized according to literature procedures (see US8426639B2 (Example 77)). The experiment was carried out according to general procedure C using cis,trans-muconic acid (43 mg, 0.3 mmol) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Levulinic acid was 1 The H NMR yield was 107%. After recalibrating the reactor temperature controller, the experiment was repeated and levulinic acid was found to be 109%. 1 H NMR yield was obtained.

[0091] Example 13: Synthesis of levulinic acid from cis,trans-muconic acid monosodium salt [Experiment No. 64] Cis,trans-muconic acid was synthesized according to literature procedures (see US8426639B2 (example 77)). The experiment was carried out according to a modified general procedure C using cis,trans-muconic acid (43 mg, 0.3 mmol), 1 M aqueous NaOH (0.3 mL, 0.3 mmol, 1 equiv.) and water (2.7 mL) at 180 °C under 15 bar N2 pressure for 3 h. Workup was performed by addition of internal standard, acetone and concentrated HCl to acidify the solution. After centrifugation, about half of the mixture was evaporated, dissolved in DMSO-d6 and analyzed by NMR. Levulinic acid was 1The 1 H NMR yield was 103%.

[0092] Example 14: Synthesis of levulinic acid cis,trans-muconic acid disodium salt [Experiment No. 65] The experiment was carried out according to a modified general procedure C with cis,trans-muconic acid (43 mg, 0.3 mmol), 1 M aqueous NaOH (0.6 mL, 0.6 mmol, 2 equiv.) and water (2.4 mL) at 180 °C under 15 bar N2 pressure for 3 h. Workup was performed by addition of internal standard, acetone and concentrated HCl to acidify the solution. After centrifugation, about half of the mixture was evaporated, dissolved in DMSO-d6 and analyzed by NMR. Levulinic acid was 96% pure. 1 1 H NMR yield was 8% for cis,trans-muconic acid. 1 Recovered in 1 H NMR yield.

[0093] Example 15: Synthesis of levulinic acid from trans,trans-muconic acid [Experiment No. 66] The experiment was carried out according to general procedure C with trans,trans-muconic acid (43 mg, 0.3 mmol) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. No levulinic acid was obtained, and trans,trans-muconic acid was obtained in 59% yield. 1 Recovered in 1 H NMR yield.

[0094] Example 16: Synthesis of levulinic acid from trans,trans-muconic acid [Experiment No. 67] The experiment was carried out according to general procedure C using trans,trans-muconic acid (43 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. Levulinic acid was dissolved in 21% 1 The trans,trans-muconic acid was obtained in the following yield by H NMR: 1 Not observed in the 1 H NMR spectrum.

[0095] Example 17: Acid concentration screening for the synthesis of levulinic acid from trans,trans-muconic acid These experiments were carried out according to general procedure C using trans,trans-muconic acid (43 mg, 0.3 mmol), the indicated amounts of HCl and water (3 mL) at 180° C. for 3 h under 15 bar N2 pressure. 1 The 1 H NMR yields (dimethylsulfone internal standard) are shown in the table below. [ka] [Table 8] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0096] Example 18: Base concentration screening for the synthesis of levulinic acid from trans,trans-muconic acid These experiments were carried out according to modified general procedure C using trans,trans-muconic acid (43 mg, 0.3 mmol), the indicated amounts of NaOH and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Work-up was performed by addition of the internal standard, acetone and concentrated HCl to acidify the solution. After centrifugation, approximately half of the mixture was evaporated, dissolved in DMSO-d6, filtered as necessary and analyzed by NMR. 1 The 1 H NMR yields (dimethylsulfone or dimethylmalonic acid internal standard) are shown in the table below. [ka] [Table 9] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0097] Example 19: Synthesis of muconolactone (2,5-dihydro-5-oxo-2-furanacetic acid) from cis,cis-muconic acid [Experiment No. 80] This reaction was modified from literature procedure US20170129839A1 (Example 3-1), starting with cis,cis-muconic acid instead of cis,trans-muconic acid. To an oven-dried round-bottom flask, cis,cis-muconic acid (355 mg, 2.5 mmol) and dry acetonitrile (25 mL) were added under argon. The suspension was stirred at 75 °C for 20 h. Afterwards, the solvent was evaporated and the crude product was purified using automated flash chromatography (Hept / EtOAc gradient + 2% AcOH; 12 g SiO2 column). Muconolactone was obtained as an off-white solid in 75% yield (268 mg, 1.88 mmol), and cis,trans-muconic acid was isolated as a by-product in 15% (52 mg, 0.37 mmol) yield.

[0098] Example 20: Synthesis of levulinic acid from muconolactone (2,5-dihydro-5-oxo-2-furanacetic acid) [Experiment No. 81] The experiment was carried out according to general procedure C using muconolactone (43 mg, 0.3 mmol) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Levulinic acid was 1 The H NMR yield was 104%. After recalibrating the temperature controller of the reactor, the experiment was repeated and levulinic acid was found to be 99% pure. 1 H NMR yield was obtained.

[0099] Example 21: Synthesis of levulinic acid from muconolactone sodium salt (sodium 2,5-dihydro-5-oxo-2-furanacetate) [Experiment No. 82] The experiment was carried out according to a modified general procedure C using muconolactone (43 mg, 0.3 mmol), 1 M aqueous NaOH (0.3 mL, 0.3 mmol, 1 equiv.) and water (2.7 mL) at 180 °C under 15 bar N2 pressure for 3 h. Workup was performed by addition of an internal standard, acetone and concentrated HCl to acidify the solution. After centrifugation, about half of the mixture was evaporated, dissolved in DMSO-d6 and analyzed by NMR. Levulinic acid was 1 The 1 H NMR yield was 108%.

[0100] Example 22: Synthesis of levulinic acid from muconic acid dilactone (tetrahydrofuro[3,2-b]furan-2,5-dione) [Experiment No. 83] Muconic acid dilactone was synthesized using literature procedures (see Hizuka, Michiyo, et al., 1988). The experiment was carried out according to general procedure C using muconic acid dilactone (43 mg, 0.3 mmol) and water (3 mL) at 180 °C under 15 bar N2 pressure for 3 h. Levulinic acid was 1 The 1 H NMR yield was 107%.

[0101] Example 23: Synthesis of 3-methyl-4-oxopentanoic acid from (2Z,4E)-3-methylhexa-2,4-dienedioic acid [Experiment No. 84] (2Z,4E)-3-methylhexa-2,4-dienedioic acid was prepared as described in the literature (Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (2Z,4E)-3-methylhexa-2,4-dienedioic acid (47 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 3-Methyl-4-oxopentanoic acid was 1 H NMR yield was 94%. TLC-MS (ESI) [MH] calculated 129.06, found 129.2. After recalibrating the reactor temperature controller, the experiment was repeated to obtain 3-methyl-4-oxopentanoic acid in 91% yield. 1 1 H NMR yield.

[0102] Example 24: Synthesis of 3-methyl-4-oxopentanoic acid from (3-methyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid [Experiment No. 85] (3-Methyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (3-methyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid (47 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 3-Methyl-4-oxopentanoic acid was 1 The H NMR yield was 99%. After recalibrating the temperature controller of the reactor, the experiment was repeated to obtain 3-methyl-4-oxopentanoic acid in 104% yield. 1 1 H NMR yield.

[0103] Example 25: Synthesis of 3-propyl-4-oxopentanoic acid from (3-propyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid [Experiment No. 86] (3-Propyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (3-propyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid (55 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 3-Propyl-4-oxopentanoic acid was 1 H NMR yield was 97%. TLC-MS (ESI) [MH] calculated 157.09, found 157.3. After recalibrating the reactor temperature controller, the experiment was repeated to give 3-propyl-4-oxopentanoic acid in 82% yield. 1 H NMR yield was obtained.

[0104] Example 26: Synthesis of 3-tert-butyl-4-oxopentanoic acid from (3-tert-butyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid [Experiment No. 87] (3-tert-Butyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (3-tert-butyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid (59 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 3-tert-Butyl-4-oxopentanoic acid was purified with 93% 1 H NMR yield: 171.10; TLC-MS (ESI) [MH] calculated 171.10; found 171.3. After recalibrating the reactor temperature controller, the experiment was repeated to obtain 3-tert-butyl-4-oxopentanoic acid in 102% yield. 1 1 H NMR yield.

[0105] Example 27: Synthesis of 3-phenyl-4-oxopentanoic acid from (3-phenyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid [Experiment No. 88] (3-Phenyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (3-phenyl-5-oxo-2,5-dihydrofuran-2-yl)acetic acid (65 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 3-Phenyl-4-oxopentanoic acid was 1 H NMR yield: 96%. TLC-MS (ESI) [MH] calculated: 191.07, found: 191.

[0106] Example 28: Synthesis of levulinic acid from (2E)-3-[2-(carboxymethyl)-5-oxo-2,5-dihydrofuran-3-yl]prop-2-enoic acid [Experiment No. 89] (2E)-3-[2-(carboxymethyl)-5-oxo-2,5-dihydrofuran-3-yl]prop-2-enoic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using (2E)-3-[2-(carboxymethyl)-5-oxo-2,5-dihydrofuran-3-yl]prop-2-enoic acid (64 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. Levulinic acid was obtained by 1 The 1 H NMR yield was 49%.

[0107] Example 29: Synthesis of levulinic acid from [3-(methoxycarbonyl)-5-oxo-2,5-dihydrofuran-2-yl]acetic acid [Experiment No. 90] [3-(Methoxycarbonyl)-5-oxo-2,5-dihydrofuran-2-yl]acetic acid was synthesized as described in the literature (see Coupe, Florentin, et al., 2020). The experiment was carried out according to general procedure C using [3-(Methoxycarbonyl)-5-oxo-2,5-dihydrofuran-2-yl]acetic acid (60 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. Levulinic acid was 1 The 1 H NMR yield was 104%.

[0108] Example 30: Temperature screening for the synthesis of methyl levulinate from cis,cis-muconic acid These experiments were carried out according to general procedure A using cis,cis-muconic acid (43 mg, 0.3 mmol) and methanol (3 mL) under 90 bar N2 pressure for 3 h. 1 The H NMR yields (1,3,5-trimethoxybenzene internal standard) are shown in the table below. [ka] [Table 10] a 1Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0109] Example 31: Additive screening for the synthesis of methyl levulinate from cis,cis-muconic acid These experiments were carried out according to general procedure C using cis,cis-muconic acid (43 mg, 0.3 mmol), the indicated additive (60 μmol, 0.2 equiv.) and methanol (3 mL) at 180 °C under 90 bar N2 pressure for 3 h. 1 The H NMR yields (1,3,5-trimethoxybenzene internal standard) are shown in the table below. [ka] [Table 11-1] [Table 11-2] a 1 Mass balance can exceed 100% since there is experimental error in each individual value determined by 1 H NMR.

[0110] Example 32: One-pot conversion of catechol to methyl levulinate [Experiment no. 131] Oxidation of catechol in air was carried out according to a modified literature procedure (see Jastrzebski, Robin, et al., 2015). A glass liner equipped with a magnetic stir bar was charged with catechol (1.101 g, 10.0 mmol), Fe(NO3)3·9H2O (20 mg, 50 μmol, 0.5 mol%), tris(2-pyridylmethyl)amine (15 mg, 20 μmol, 0.5 mol%) and 1,4-diazabicyclo[2.2.2]octane (112 mg, 1.0 mmol, 10 mol%) in methanol (100 mL). The liner was placed in a 4651 Parr reactor. The reactor was properly closed, flushed with synthetic air (10 bar), then pressurized with synthetic air (25 bar), all vigorously stirred. The reactor was heated to 80 °C in 30 min and held at that temperature for 4 h.

[0111] The heating was stopped and the reactor was cooled in an ice bath for about 45 min. The reactor was then vented, flushed with nitrogen (3×30 bar) and pressurized with nitrogen (85 bar). It was heated to 180° C. in 1 h and held at that temperature for 3 h. The heating was then stopped and the reactor was cooled overnight. The reaction mixture was evaporated to a volume of less than 50 mL and then partitioned between 100 mL of EtOAc and 100 mL of 1 M aqueous HCl. The phases were separated and the aqueous layer was washed again with 2×100 mL of EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 (50 mL) was dried over MgSO4, concentrated and purified using automated flash chromatography (40 g SiO2 column, Hept / EtOAc gradient) to give methyl levulinate as a yellow oil in 16% (210 mg, 1.61 mmol) yield.

[0112] Example 33: Synthesis of 2-methyl-4-oxopentanoic acid from (2Z,4Z)-2-methylhexa-2,4-dienedioic acid [Experiment No. 132] (2Z,4Z)-2-Methylhexa-2,4-dienedioic acid was prepared as described in the literature, see Coupe, Florentin, et al., 2020. The experiment was carried out according to general procedure C with (2Z,4Z)-2-methylhexa-2,4-dienedioic acid (47 mg, 0.3 mmol) and water (3 mL) at 250 °C under 50 bar N2 pressure for 3 h. 2-Methyl-4-oxopentanoic acid was dissolved in 60% 1 1H NMR yield of 14% 4-oxohexanoic acid. 1 Obtained as a by-product by H NMR yield. TLC-MS (ESI) [MH] calculated 129.06, found 129.

[0113] Example 34: Solvent and additive screening for the synthesis of methyl levulinate from cis,cis-muconic acid These experiments were carried out according to general procedure C using cis,cis-muconic acid (43 mg, 0.3 mmol), the indicated additive (60 μmol, 0.2 equiv.) and alkyl alcohol (3 mL) at 180 °C under 80 bar N2 pressure for 3 h. 1 The H NMR yields (1,3,5-trimethoxybenzene internal standard) are shown in the table below. [ka] [Table 12]

[0114] References 1.Coupe, Florentin, et al. "Sustainable oxidative cleavage of catechols for the synthesis of muconic acid and muconolactones including lignin upgrading." Green Chemistry 22.18 (2020): 6204-6211. 2.US8426639B2, “Preparation of trans, trans muconic acid and trans, trans muconates”, example 77. 3.US20170129839A1 “ISOMERIZATION OF MUCONIC ACID”, example 3-1. 4.Hizuka, Michiyo, et al., "Preparation of 2, 6-Dioxabicyclo [3.3.0] octan-3,7-dione and Its Application to the Synthesis of (±)-Eldanolide." Chemical and pharmaceutical bulletin 36.4 (1988): 1550-1553. 5.Jastrzebski, Robin, et al. "Sustainable production of dimethyl adipate by non-heme iron (III) catalysed oxidative cleavage of catechol." Catalysis Science & Technology 5.4 (2015): 2103-2109.

Claims

1. A method for producing levulinic acid, or a salt or levulinic acid ester thereof, comprising the steps of: a) polar protic solvents, and a muconic compound selected from the list comprising muconic acid, muconate salts, muconic acid esters, mucono(di)lactone and represented by general formula (I): 【Chemistry 1】 In the general formula (I): - A1, A2 are independently selected from the list comprising H, alkyl and cation; - R1, R2, R3, R4 are independently selected from the list comprising H, alkyl, alkenyl, carboxyl, aryl, and at least one of R2, R3 is H; - R1C-CR2 and R3C-CR4 are double C-C bonds; and according to these conditions, the formula (IA): 【Chemistry 2】 or a mucon compound shown in In the general formula (I): A 1 represents a direct bond connecting the oxygen to which it is attached to the carbon atom in position R 3 , thereby forming a five-membered ring; A 2 is selected from the list comprising H, alkyl and cations; - R1, R2, R4 are independently selected from the list comprising H, alkyl, alkenyl, carboxyl, aryl; - R1C-CR2 is a double C-C bond and R3C-CR4 is a single C-C bond; 【Chemistry 3】 or a mucon compound shown in In the general formula (I): - A 1 and A 2 each represent a direct bond connecting the oxygen to which they are attached to the carbon atom at the R 3 and R 2 positions, respectively, thereby forming a fused system of two 5-membered rings; - R1, R4 are independently selected from the list comprising H, alkyl, alkenyl, carboxyl, aryl; - R1C-CR2 and R3C-CR4 are single C-C bonds; and according to these conditions, the formula (IC): 【Chemistry 4】 Mucon compounds shown in providing a reaction mixture comprising: b) - the reaction mixture provided in step a) is heated to a temperature T of at least about 120° C. i And the pressure P i ≧autogenous pressure, thereby preparing levulinic acid, or a salt thereof, or a levulinate ester, The levulinic acid, or a salt or levulinic acid ester thereof, is a compound represented by formula (II): 【Chemistry 5】 During the ceremony, - B is selected from the group comprising H, alkyl, inorganic cations, organic cations; and - R5, R6 are selected from the group including, but not limited to, H, alkyl, alkenyl, carboxyl, aryl, A method comprising:

2. 2. The process according to claim 1, wherein step b) comprises heating the reaction mixture at a temperature Ti of at least 160° C. or at least 180° C.

3. 3. The method according to claim 1 or 2, wherein in step a) the polar protic solvent is water.

4. The method according to claim 3, wherein in step a) the water does not contain any basic or acidic additives, so that the pH of the reaction mixture is not adjusted and is different from the pH of the reaction mixture provided by the mucon compound or the compound alone.

5. The method of claim 3, wherein in step a) the reaction mixture consists of water and one or more mucon compounds.

6. 3. The process according to claim 1 or 2, wherein the polar protic solvent is an alkyl alcohol selected from the list comprising methanol, ethanol, isopropanol, propanol and butanol.

7. The method according to claim 6, wherein in step a) the polar protic solvent is methanol.

8. The method of claim 6 , wherein the reaction mixture further comprises a basic catalyst.

9. 9. The method of claim 8, wherein the basic catalyst comprises one or more sp3 hybridized nitrogen atoms.

10. 9. The process according to claim 8, wherein the basic catalyst is selected from the list comprising diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene.

11. The method according to claim 1 or 2, wherein the mucon compound is a mucon compound represented by formula (IA).

12. 3. The method according to claim 1 or 2, wherein in step a) the mucone compound is a mucone compound of cis,cis-, cis,trans- or trans,cis-configuration, or a mucone compound of cis,cis-configuration.

13. 3. The process of claim 1 or 2, wherein step b) comprises heating the reaction mixture in a non-oxidizing atmosphere.

14. 3. The process according to claim 1 or 2, wherein steps a) and b) are carried out successively without isolating any intermediate.

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