Process for preparing at least partially acetal protected sugar

Abstract

The invention relates to a method for preparing an at least partially acetal-protected sugar, involving the step of reacting a sugar or a sugar derivative selected from the group consisting of valeraldoses, hexanoses, valeraldoglycosides and hexanoglycosides with an aldehyde or a source of aldehyde in the presence of a heterogeneous acidic catalyst, forming an at least partially acetal-protected sugar selected from the group consisting of compounds of formulae (I), (II), (III), (IV), (V), (VI,) (VII), (VIII), (IX), (X), (XI) and (XII), # imgabs0, r1, R1 ', R2, R2', R3, R3 ', R4, R5, R6, R7, R8, R9, R10, R11, R12 and R12' are Y or Z-E, where R1 and R1 ', R2 and R2', R3 and R3 ', R12 and R12' are equal to or different from each other and Y is hydrogen or a linear, branched or cyclic hydrocarbon moiety having 1 to 20 carbon atoms, Z is a linear, branched or cyclic hydrocarbon moiety having 0 to 12 carbon atoms, optionally substituted with 1 to 4 C1 to C4 alkyl groups, 1 to 4 halogen atoms or benzyl groups, e is-COOH,-CH (COOH) 2,-COOR19,-CH (COOR20) (COOR21),-CHO,-CH (CHO) 2,-C2H3, CH (C2H3) 2,-CHCHR22,-CHCR23R24,-C2H,-C2R25,-N3,-NH2,-CH (NH2) 2,-NHR26,-CH (NHR27) (NHR28),-NR29R30,-CH (NR36OH),-OH,-OR35,-CH (R36OH), and R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R32, R33, R34 and R37OH and R13, R14, R15, R16, R17 and R18 are each independently hydrogen or a linear, branched or cyclic hydrocarbon moiety having 1 to 20 carbon atoms.

Description

[0001] The present invention relates to a method for preparing at least partially acetal - protected sugars.

[0002] In recent decades, the gradual depletion of fossil fuel resources, the increasing global energy consumption, and environmental problems have driven the development of new materials and new technologies that utilize renewable biogenic sources such as biomass or food waste. One of the forefront topics in this field is the development of biobased chemicals, which are regarded as greener alternatives to petroleum - derived chemicals. In principle, biobased chemicals generally do not cause a net increase in carbon dioxide in the atmosphere at the end of their service life, thus ensuring less environmental damage.

[0003] WO2022 / 223480 discloses acetal - protected xylose - diformylxylose (DFX) and its derivatives as green polar aprotic solvents. Example 1 shows a synthetic route using a homogeneous acidic catalyst (H2SO4) from commercially available D - xylose and paraformaldehyde, and this catalyst must be added dropwise to avoid sugar degradation.

[0004] WO2021074211 discloses a method for preparing polymerizable monomers from renewable resources such as biomass. Studies have shown that in the presence of a homogeneous acidic catalyst, xylose protected by glyoxylic acid can be produced. The glyoxylic - acid - protected xylose can be used in polymer synthesis.

[0005] Y.M. Questell - Santiago, R. Zambrano - Varela, M. Talebi Amiri and J.S. Luterbacher, Nat.Chem. 2018, 10, 1222 - 1228 disclose that DFX can be directly synthesized from D - xylose using 1,4 - dioxane as a solvent and n - hexane as an extraction solvent in the presence of 37 wt% aqueous formaldehyde solution and 37 wt% aqueous HCl solution.

[0006] All methods require continuous addition and neutralization of homogeneous acids, which is not conducive to large - scale processing due to increased costs and waste management.

[0007] The object of the present invention is to provide a more convenient method for preparing acetal - protected sugars in high yield using a scalable method.

[0008] The method according to claim 1 can solve this problem. Dependent claims 2 to 15 list more preferred embodiments.

[0009] It has been found that at least a part of the method for acetal - protected sugars can be prepared by a method involving the following steps: reacting a sugar or sugar derivative selected from pentoses, hexoses, pentosides, and hexosides with an aldehyde or aldehyde source in the presence of a heterogeneous acid catalyst to form at least a part of an acetal - protected sugar selected from compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII,

[0010]

[0011]

[0012]

[0013] wherein, R1, R1’, R2, R2’, R3, R3’, R4, R 5、 R6, R7, R8, R9, R 10 、R 11 、R 12 and R 12 ’ are Y or Z - E, where R1 and R1’, R2 and R2’, R3 and R3’, R 12 and R 12 ’ are the same as or different from each other, and

[0014] Y is hydrogen or a straight - chain, branched - chain, or cyclic hydrocarbon moiety having 1 to 20 carbon atoms,

[0015] Z is a straight - chain, branched - chain, or cyclic hydrocarbon moiety having 0 to 12 carbon atoms, optionally substituted with 1 to 4 C1 - C4 alkyl groups, 1 to 4 halogen atoms, or benzyl, and

[0016] E is - COOH, - CH(COOH)2, - COOR 19 、- CH(COOR 20 )(COOR 21 )、- CHO, - CH(CHO)2, - C2H3, CH(C2H3)2, - CHCHR 22 、- CHCR 23 R 24 、- C2H, - C2R 25 、- N3, - NH2, - CH(NH2)2, - NHR 26 、- CH(NHR 27 )(NHR 28 )、- NR 29 R 30 、- CH(NR 31 R 32 )(NR 33 R 34 )、- OH, - OR35 , -CH(R 36 OH)(R 37 OH), and

[0017] R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 are each independently C1 to C 20 alkyl, and

[0018] R 20 and R 21 , R 23 and R 24 , R 27 and R 28 , R 29 and R 30 , R 31 and R 32 , and R 33 and R 34 are the same as or different from each other, and

[0019] R 36 and R 37 are each independently absent or a straight-chain or branched-chain C1 to C 12 hydrocarbon chain, and

[0020] R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen or a straight-chain, branched-chain or cyclic hydrocarbon moiety having 1 to 20 carbon atoms.

[0021] By using a heterogeneous acidic catalyst, the need for continuous addition and neutralization of homogeneous acid can be reduced. The catalyst can be easily recycled, for example, by filtration, which has advantages in terms of economy and environmental protection. In addition, the catalyst can also be used as a packing in a continuous flow reactor for large-scale production. Compared with conventional homogeneous catalyst systems (such as HCl or H2SO4), the yield and selectivity of acetal-protected sugars can also be improved.

[0022] In addition, although aldehydes have high reactivity during the reaction, prone to undesirable aldol condensation, oxidation, self-polymerization, and formation of gem-diols, in the presence of a heterogeneous catalyst, compounds of Formulas I to XII can be obtained. Moreover, the unique hydrate formation property of aldehydes allows controlling the rate and selectivity of sugar protection by regulating the water content in the reaction system.

[0023] Heterogeneous catalysts with different pore sizes and affinities for reactants and products can further improve the selectivity of acetal-protected sugars. Using a heterogeneous catalyst with small pores can enhance the selectivity for small products. For example, relative to the compounds of Formulas I, II, III, and XII, selectively form the compounds of Formulas IV to XI, or relative to those with larger R groups (selected from R1, R1’, R2, R2’, R3, R3’, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、and R 12 ’), selectively form the compounds of Formulas I to XII with smaller R groups (selected from R1, R1’, R2, R2’, R3, R3’, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、and R 12 ’). Conversely, using a heterogeneous catalyst with large pores will increase the selectivity for large products. For example, relative to the compounds of Formulas IV to XI, selectively form the compounds of Formulas I, II, III, and XII, or relative to those with smaller R groups, selectively form the compounds of Formulas IV to XI with larger R groups. Similarly, the selectivity can also be finely regulated by the affinity between the aldehyde and the heterogeneous catalyst. A high affinity between the aldehyde and the heterogeneous catalyst results in higher selectivity for forming the compounds of Formulas I, II, III, and XII relative to the compounds of Formulas IV to XI. A low affinity between the aldehyde and the heterogeneous catalyst leads to higher selectivity for forming the compounds of Formulas IV to XI relative to the compounds of Formulas I, II, III, and XII.

[0024] Certain compounds produced by the methods of the present invention can be used as green polar aprotic solvents. Among those compounds that can be used as such solvents, some compounds have comparable or better properties compared to conventional fossil-based analogues. In addition, they have many other applications. For example, they can be used as platform molecules for the production of many other biobased products, and thus, their efficient production is very important. For example, DFX can be used as a starting compound for the production of the food additive xylitol. Partially acetal-protected sugars having long-chain hydrocarbon aldehydes (such as alkyl or alkenyl aldehydes) can also be used as biobased surfactants. Fully protected sugars having esters, carboxyl groups, or hydroxyl groups in the corresponding R groups can be used as building blocks for polymer production.

[0025] In the context of the present invention, the term "pentose" refers to a pentose sugar having an aldehyde functional group at the terminal carbon atom, and is preferably selected from the group consisting of D-ribose, L-ribose, D-arabinose, L-arabinose, D-xylose, L-xylose, D-lyxose, and L-lyxose. Due to the tautomerism of the sugar, the pentose can be used in the form of a straight-chain, pyranose, or furanose conformation, or a mixture thereof.

[0026] In the context of the present invention, the term "hexose" refers to a hexose sugar having an aldehyde functional group at the outermost carbon atom, and is preferably selected from the group consisting of D-allose, L-allose, D-altrose, L-altrose, D-glucose, L-glucose, D-mannose, L-mannose, D-gulose, L-gulose, D-idose, L-idose, D-galactose, L-galactose, D-talose, and L-talose. Due to the tautomerism of the sugar, the hexose can be used in the form of a straight-chain, pyranose, or furanose conformation, or a mixture thereof.

[0027] In the context of the present invention, the term "pentaldoside" refers to a pentose as defined above, wherein the oxygen atom at the 1-position of the aldopentose is linked via a glycosidic bond to a functional group (preferably a C1 to C4 alkyl group) of a straight-chain, branched-chain or cyclic hydrocarbon moiety having from 1 to 20 carbon atoms, thereby forming a 1-O-alkyl aldopentose. It is preferably selected from the group consisting of: 1-O-alkyl-D-ribose, 1-O-alkyl-L-ribose, 1-O-alkyl-D-arabinose, 1-O-alkyl-L-arabinose, 1-O-alkyl-D-xylose, 1-O-alkyl-L-xylose, 1-O-alkyl-D-lyxose, 1-O-alkyl-L-lyxose, and the alkyl group is preferably selected from the group consisting of methyl, ethyl, propyl, and butyl, most preferably methyl. Most preferably, the pentaldoside is 1-O-methyl-D-xylose. Due to the tautomerism of the sugar, the alkyl aldopentose can be used in the form of a straight-chain, pyranose or furanose conformation or a mixture thereof. Due to the additional protection of the hydroxyl group at the 1-position of the sugar, the starting material can more easily produce a monofunctional acetal monomer containing a free hydroxyl group. In this way, a bifunctional monomer (for example, a hydroxy acid is formed if glyoxylic acid is used) can be produced.

[0028] In the context of the present invention, the term "hexaldoside" refers to a hexose as defined above, wherein the oxygen atom at the 1-position of the aldohexose is linked via a glycosidic bond to a functional group (preferably a C1 to C4 alkyl group) of a straight-chain, branched-chain or cyclic hydrocarbon moiety having from 1 to 20 carbon atoms, thereby forming a 1-O-alkyl aldohexose. It is preferably selected from the group consisting of: 1-O-alkyl-D-allose, 1-O-alkyl-L-allose, 1-O-alkyl-D-altrose, 1-O-alkyl-L-altrose, 1-O-alkyl-D-glucose, 1-O-alkyl-L-glucose, 1-O-alkyl-D-mannose, 1-O-alkyl-L-mannose, 1-O-alkyl-D-gulose, 1-O-alkyl-L-gulose, 1-O-alkyl-D-idose, 1-O-alkyl-L-idose, 1-O-alkyl-D-galactose, 1-O-alkyl-L-galactose, 1-O-alkyl-D-talose and 1-O-alkyl-L-talose, and the alkyl is preferably selected from methyl, ethyl, propyl and butyl, most preferably methyl. Most preferably, the hexaldoside is 1-O-methyl-D-glucose. Due to the tautomerism of the sugar, the alkyl aldohexose can be used in the form of a straight-chain, pyranose or furanose conformation or a mixture thereof. Due to the additional protection of the hydroxyl group at the 1-position of the sugar, the starting material produces a more stable -OH-free product, which can be used for the production of linear polymers.

[0029] The term "at least partially acetal - protected sugar" refers to a sugar or sugar derivative selected from the group consisting of pentoses, hexoses, pentosides, and hexosides, which is either partially protected by an aldehyde, i.e., only two hydroxyl groups together with the aldehyde form a cyclic acetal (thus forming a compound of formula IV, V, VI, VII, VIII, IX, X, or XI); or completely protected by an aldehyde, i.e., four hydroxyl groups together with two aldehydes form two corresponding cyclic acetals (thus forming a compound of formula I, II, III, or XII).

[0030] An aldehyde is an organic compound containing a - CHO group, and an aldehyde source is a polymeric or oligomeric compound capable of generating an aldehyde under the reaction conditions. The term "aldehyde" also includes the gem - diol of the corresponding aldehyde, i.e., the aldehyde hydrate.

[0031] One embodiment of the present invention relates to the production of fully protected compounds selected from the group consisting of compounds I, II, III, and VII:

[0032]

[0033]

[0034] In one embodiment of the present invention, R 13 、R 14 、R 15 、R 16 and R 17 are all hydrogen, thus obtaining an at least partially protected compound selected from compounds IVa, VIa, VIIIa, Xa, and XIa:

[0035]

[0036]

[0037] In one embodiment of the present invention, R 13 、R 14 、R 15 、R 16 and R 17 are straight - chain, branched - chain, or cyclic hydrocarbon moieties having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, most preferably methyl, ethyl, propyl, and butyl, and ideally methyl, thus obtaining an at least partially protected compound selected from compounds IVb, VIb, VIIIb, Xb, XIb, and XII:

[0038]

[0039]

[0040] In one embodiment of the present invention, R1, R1', R2, R2', R3, R3', R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 12 ' in Compounds I to XII are Y, and Y is hydrogen.

[0041] In another embodiment of the present invention, R1, R1', R2, R2', R3, R3', R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 12 ' in Compounds I to XII are Y, and are selected from linear or branched C1 to C 20 alkyl, linear or branched C2 to C 20 alkenyl, cycloaliphatic rings or aromatic systems and combinations thereof, preferably C6 to C 20 alkyl and combinations thereof.

[0042] The term "linear or branched C1 to C 20 alkyl" refers to a linear or branched hydrocarbon group containing 1 to 20 carbon atoms. Examples of "alkyl" as used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.

[0043] The term "linear or branched C2 to C 20 alkenyl" refers to a linear or branched hydrocarbon group containing 2 to 20 carbon atoms and having at least one carbon-carbon double bond. Examples of "alkenyl" as used herein include vinyl, propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and isobutenyl.

[0044] The term "cycloaliphatic ring or aromatic system" refers to a cycloaliphatic or aromatic ring system having 3 to 10, preferably 5 to 8 carbon atoms.

[0045] In one embodiment of the present invention, R1, R1', R2, R2', R3, R3', R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 12’ is Z-E, where,

[0046] Z is a straight-chain, branched-chain or cyclic hydrocarbon moiety having 0 to 12 carbon atoms, optionally substituted with 1 to 4 C1-C4 alkyl groups, 1 to 4 halogen atoms or benzyl, and

[0047] E is -COOH, -CH(COOH)2, -COOR 19 , -CH(COOR 20 )(COOR 21 ), -CHO, -CH(CHO)2, -C2H3, CH(C2H3)2, -CHCHR 22 , -CHCR 23 R 24 , -C2H, -C2R 25 , -N3, -NH2, -CH(NH2)2, -NHR 26 , -CH(NHR 27 )(NHR 28 ), -NR 29 R 30 , -CH(NR 31 R 32 )(NR 33 R 34 ), -OH, -OR 35 , -CH(R 36 OH)(R 37 OH), and

[0048] R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 are each independently C1-C 20 alkyl, and

[0049] R 20 and R 21 , R 23 and R 24 , R 27 and R 28 , R 29 and R 30 , R31 and R 32 , and R 33 and R 34 are the same as or different from each other, and

[0050] R 36 and R 37 are each independently absent or a straight-chain or branched C1 to C 12 hydrocarbon chain, and

[0051] R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are each independently hydrogen or a straight-chain, branched or cyclic hydrocarbon moiety having 1 to 20 carbon atoms.

[0052] According to one embodiment of the present invention, among I, II, III, IV (IVa and IVb), V, VI (VIa and VIb), VII, VIII (VIIIa and VIIIb), IX, X (Xa and Xb), XI (XIa and XIb) and XII, Z-E is preferably:

[0053] -(CH2) m COOH; -C6H4COOH, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 COOH, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups; -(CH2) m CH(COOH)2;

[0054] -(CH2) m COOR 19 ; -C6H4COOR 19 , wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 COOR 19 , wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0055] -(CH2) m CH(COOR 20 )(COOR 21 ); -C6H4CH(COOR 20 )(COOR 21 ), wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 CH(COOR 20 )(COOR 21), wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0056] -(CH2) m CHO; -C6H4CHO, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 CHO, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups or 14 halogen atoms; -(CH2) m CH(CHO)2;

[0057] -(CH2) m C2H3; -C6H4C2H3, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 C2H3, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups; -(CH2) m CH(C2H3)2;

[0058] -(CH2) m CHCHR 22 ; -C6H4CHCHR 22 ), wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 CHCHR 22 ), wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0059] -(CH2) m CHCR 23 R 24 ; -C6H4CHCR 23 R 24 ), wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 CHCR 23 R 24 ), wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0060] -(CH2) m C2H; -C6H4C2H, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 C2H, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0061] -(CH2) m C2R 25 ; -C6H4C2R 25, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 C2R 25 , wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0062] -(CH2) m N3; -C6H4N3, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 N3, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0063] -(CH2) m NH2; -C6H4NH2, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 NH2, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups; -(CH2) m CH(NH2)2;

[0064] -(CH2) m NHR 26 ; -C6H4NHR 26 , wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 NHR 26 , wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0065] -(CH2) m NR 29 R 30 ; -C6H4NR 29 R 30 , wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 NR 29 R 30 , wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0066] -(CH2) m CH(NR 31 R 32 )(NR 33 R 34 ); -C6H4 CH(NR 31 R 32 )(NR 33 R 34 ), wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H10 CH(NR 31 R 32 )(NR 33 R 34 ), wherein the aliphatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups;

[0067] -(CH2) m OH; -C6H4OH, wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 OH, wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0068] -(CH2) m OR 35 ;-C6H4OR 35 , wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 OR 35 , wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0069] -CH(R 36 OH)(R 37 OH); -C6H4CH(R 36 OH)(R 37 OH), wherein the aromatic ring is optionally substituted with 1 to 4 C1-C4 alkyl groups or 1 to 4 halogen atoms; -C6H 10 CH(R 36 OH)(R 37 OH), wherein the aliphatic ring is optionally substituted with 1 to 10 C1-C4 alkyl groups;

[0070] R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 and R 35 Each independently is C1 to C 20 Alkyl, and

[0071] R 20 and R 21 , R23 and R 24 、R 27 and R 28 、R 29 and R 30 、R 31 and R 32 、and R 33 and R 34 are the same as or different from each other, preferably methyl, ethyl, propyl and butyl, and

[0072] R 36 and R 37 are independent of each other or do not exist (e.g., -CH(OH)2 or CH(OH)CH2OH)) or are straight-chain or branched C1 to C 12 hydrocarbon chains, preferably methylene, ethylene, propylene or butylene.

[0073] m is an integer from 0 to 12, especially an integer from 0 to 4.

[0074] In the context of the present invention, the term "heterogeneous acid catalyst" means that the acid catalyst is in the solid phase and the reactants are in the liquid phase. Preferably, the acid catalyst is a Bronsted acid catalyst, more preferably an anhydrous Bronsted acid catalyst. More specifically, this can be a heterogeneous acid material and / or an optional Bronsted acid catalyst, which can be embedded, loaded or covalently bonded to a solid support, such as resin beads, membranes, porous carbon particles, zeolite materials and other solid supports. For example, the solid support can be a material including carbon, silica, titanium dioxide, zirconium oxide, alumina or any combination of these oxides.

[0075] Bronsted acids are capable of providing protons and are known to those skilled in the art. For example, Bronsted acids can be bridging hydroxyl groups of zeolites or Bronsted acid site-functionalized resins. Bronsted acids useful for resin functionalization are preferably selected from the group consisting of sulfuric acid, phosphoric acid and methanesulfonic acid or mixtures thereof.

[0076] Preferably, the Bronsted acid catalyst is selected from the group consisting of:

[0077] a. acidic zeolites,

[0078] b. acid-doped zeolites,

[0079] c. acid site-functionalized resins,

[0080] d. acid site-functionalized oxides,

[0081] e. acidic oxides,

[0082] f. heteropolyacids and their derivatives.

[0083] As used herein, the term "acid site-functionalized resin" refers to a resin or polymer synthesized from an organic polymer matrix and used as an ion exchange medium. For example, the organic polymer matrix is sulfonated polystyrene divinylbenzene or sulfonated tetrafluoroethylene-based fluoropolymer-copolymer, thereby forming a strong acid cation exchange resin or polymer. Non-limiting examples include Amberlyst-15, Amberlyst-36, Amberlyst-XNIOIO, Amberlite (e.g., Amberlite IRC120), Dowex D 2030, Nafion NR50, and Nafion SAC13.

[0084] The term "acid site-functionalized oxide" refers to an oxide that, after functionalization, can produce, for example, a sulfated or sulfonated material, such as zirconia, alumina, or silica. Such solid-state acidic metal oxides can optionally be supported on a carrier material.

[0085] The term "acidic oxide" refers to a metal oxide that has Bronsted acidity, such as niobium oxide or alumina.

[0086] The term "zeolite" as used herein refers to natural and synthetic microporous crystalline silicate materials (including aluminosilicates, borosilicates, and aluminoborosilicates) having a defined crystal structure determinable by X-ray diffraction. Zeolites contain a channel system that can be interconnected with other channel systems or cavities (such as side pockets or cages). The channel system can be three-dimensional, two-dimensional, or one-dimensional. Zeolites contain SiO4 and XO4 tetrahedra, where X can be Al (aluminum) or B (boron). Zeolites can contain a combination of AlO4 and BO4 tetrahedra. In one embodiment, X is Al and the zeolite does not contain BO4 tetrahedra. The corners of the SiO4 and XO4 tetrahedra are joined together by a common oxygen atom. The Atlas of Zeolite Framework Types (C Baerlocher, LB McCusker, DH Olson, 6th ed. Elsevier, Amsterdam, 2007) in conjunction with the web-based version (“http: / / www.iza-structure.org / databases / ”) is a compilation of zeolite framework topologies and structural details, which includes the types of ring structures present in zeolites and the channel dimensions defined by each ring structure. Verified recipes for zeolite synthesis and good laboratory practices can be found in “Verified synthesis of zeolitic materials” 2nd ed. 2001. There are currently a variety of proven methods for synthesizing BO tetrahedra. For example, Cichocki and Parasiewicz-Kaczmarska described the synthesis and properties of boron-based zeolites with MFI topology (Zeolites 1990, 10, 577-582).

[0087] Zeolites suitable for the processes of the present invention can include:

[0088] - at least two, preferably two or three, non-interconnected parallel channel systems, wherein at least one of said systems contains channels with rings of more than 8 members; and the framework Si / X2 ratio measured by NMR is at least 4; or

[0089] - at least two, preferably two or three, interconnected non-parallel channel systems, wherein at least one of said systems contains channels with rings of more than 10 members; and the framework Si / X2 ratio measured by NMR is at least 4; or

[0090] - three interconnected non-parallel channel systems, wherein at least two of the channel systems contain channels with rings of more than 10 members, and the framework Si / X2 ratio measured by NMR is at least 4.

[0091] Each X is Al or B.

[0092] As used herein, the term "channel system" refers to a system of channels that are parallel or non - parallel and crystallographically equivalent, where the channels are 8 - membered ring channels or larger channels, e.g., 10 - membered ring channels or 12 - membered ring channels. Thus, as used herein, the term "channel" refers to a channel of more than 8 - membered rings, which is part of a system of channels that are parallel or non - parallel and crystallographically equivalent.

[0093] The zeolites suitable for this process contain channels of more than 10 - membered rings, e.g., 12 - membered ring channels (12MR) or larger channels. The ring sizes of each known zeolite framework type are provided in Atlas of Zeolite Framework Types (C Baerlocher, LB McCusker, DH Olson, 6th Edition. Elsevier, Amsterdam, 2007), which is hereby incorporated by reference.

[0094] As used herein, the term "8 - membered ring channel" or "8MR" refers to an unobstructed 8 - membered ring channel, where the 8 - membered ring channel defines the minimum diameter of the channel. An 8 - membered ring contains 8 T atoms and 8 alternating oxygen atoms (forming the ring), where each T atom is Si, Al, or B. As used herein, the term "10 - membered ring channel" or "10MR" refers to an unobstructed 10 - membered ring channel, where the 10 - membered ring channel defines the minimum diameter of the channel. A 10 - membered ring contains 10 T atoms and 10 alternating oxygen atoms (forming the ring), where each T atom is Si, Al, or B. As used herein, the term "12 - membered ring channel" or "12MR" refers to an unobstructed 12 - membered ring channel, where the 12 - membered ring channel defines the minimum diameter of the channel. A 12 - membered ring contains 12 T atoms and 12 alternating oxygen atoms (forming the ring), where each T atom is Si, Al, or B. As used herein, "channels of more than 10 - membered rings" refers to 10 - membered ring channels or larger channels, and thus includes, for example, 10 - membered ring channels and 12 - membered ring channels.

[0095] The framework Si / X2 ratio can be determined by nuclear magnetic resonance (NMR) measurements, more particularly, 29 Si and 27Determined by Al NMR. In a preferred embodiment, there is no framework B and the Si / X2 ratio is equal to the Si / Al2 ratio. The Si / Al2 ratio can be determined by NMR as described by Klinowski (Ann. Rev. Mater. Sci. 1988, 18, 189 - 218); or as described by G. Engelhardt and D. Michel (High-Resolution Solid-State NMR of Silicates and Zeolites. John Wiley & Sons, Chichester 1987. xiv, 485 pages). The Si / B2 ratio can be determined by NMR as discussed by D. Trong On et al. (Studies in Surface Science and Catalysis 1995, 97, 535 - 541; Journal of Catalysis, November 1995, Vol. 157, No. 1, pp. 235 - 243).

[0096] Zeolites are thermally stable catalysts and can thus be regenerated by calcination, which is different from conventional thermally stable ion exchange resins such as Amberlyst-15.

[0097] As used herein, the term "heteropolyacid" refers to a compound comprising:

[0098] - a metal selected from the group consisting of tungsten, molybdenum, and vanadium;

[0099] - p-block elements of the periodic table, such as silicon, phosphorus, or arsenic;

[0100] - oxygen and

[0101] - hydrogen.

[0102] Preferably, the heteropolyacid is selected from the group consisting of phosphotungstic acid, silicotungstic acid, arsenotungstic acid, phosphomolybdic acid, silicomolybdic acid, arsenomolybdic acid, phosphovanadic acid, silicovanadic acid, and arsenovanadic acid. In another preferred embodiment, the heteropolyacid derivative is produced by conventional derivatization techniques to render it solidified / immobilized, particularly including its salts and forms immobilized on a solid support or resin beads.

[0103] In one embodiment of the present invention, the process comprises the step of contacting a pentose or hexose and an aldehyde or aldehyde source with an acidic zeolite, wherein the zeolite comprises:

[0104] - at least two, preferably two or three non-connected parallel channel systems, wherein at least one of said systems comprises channels with rings of more than 8 members; and the framework Si / X2 ratio measured by NMR is at least 4; or

[0105] - At least two, preferably two or three, interconnected non-parallel channel systems, where at least one of the systems contains channels with rings of more than 10 members; and the framework Si / X2 ratio measured by NMR is at least 4; or

[0106] - Three interconnected non-parallel channel systems, where at least two of the channel systems contain channels with rings of more than 10 members, and the framework Si / X2 ratio measured by NMR is at least 4,

[0107] where each X is Al or B.

[0108] The zeolite contains three interconnected non-parallel channel systems, where at least two of the channel systems contain channels with rings of more than 10 members, and the framework Si / X2 ratio measured by NMR is at least 4, thereby obtaining excellent results.

[0109] The term "channel system" preferably refers to a parallel crystallographically equivalent channel system, where the channels are 8-membered ring channels or larger channels.

[0110] Good results can be obtained using zeolites containing at least two interconnected non-parallel channel systems (two-dimensional or three-dimensional microporous geometries). Thus, the zeolites used in the processes described herein have two-dimensional or three-dimensional microporous geometries, more particularly interconnected two-dimensional or three-dimensional microporous geometries.

[0111] Good results have also been achieved with zeolites containing at least one channel with a ring of more than 10 members.

[0112] Thus, in a specific embodiment, the zeolite used in the processes described herein can have: a framework Si / X2 ratio of at least 4, for example, a framework Si / Al2 ratio of at least 4, where the zeolite further contains at least two, preferably two or three, non-interconnected parallel channel systems, where at least one of the channel systems contains channels with rings of more than 8 members. An example of such a zeolite is, but not limited to, a zeolite with a mordenite (MOR) topology.

[0113] In certain embodiments, the zeolite used in the processes described herein can have: a framework Si / X2 ratio of at least 4, for example, a framework Si / Al2 ratio of at least 4, where the zeolite also contains at least two interconnected non-parallel channel systems, where at least one of the interconnected non-parallel channel systems contains channels with rings of more than 10 members, i.e., at least one channel system contains channels with rings of more than 10 members, and at least one other channel system contains channels with rings of more than 8 members.

[0114] In certain embodiments, the zeolite used in the processes described herein may have a framework Si / X2 ratio of at least 4, e.g., a framework Si / Al2 ratio of at least 4, wherein the zeolite further comprises at least three interconnected non-parallel channel systems, wherein at least two of the interconnected non-parallel channel systems comprise channels with rings of more than 10 members, i.e., at least two channel systems comprise channels with rings of more than 10 members, and another channel system comprises channels with rings of more than 8 members. Examples of such zeolites include, but are not limited to, zeolites having a topology selected from the group consisting of BEA, FAU, and MEL.

[0115] In a specific embodiment, the zeolite comprises at least two non-interconnected parallel channel systems, wherein at least one of the non-interconnected parallel channel systems comprises channels with rings of more than 8 members; wherein the zeolite further has a framework Si / X2 ratio of at least 4, more particularly at least 4, e.g., a ratio of at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., at least 50, e.g., at least 60, e.g., at least 70, e.g., at least 80, e.g., at least 90, or e.g., at least 100, or e.g., at least 110, or e.g., at least 120, or e.g., at least 130, or e.g., at least 140, or e.g., at least 150, or e.g., at least 160, or e.g., at least 170, or e.g., at least 180, or e.g., at least 190, or e.g., at least 200.

[0116] In a specific embodiment, the zeolite comprises at least two, preferably two or three, interconnected non-parallel channel systems, wherein at least one of the interconnected non-parallel channel systems comprises channels with rings of more than 10 members; wherein the zeolite further has a framework Si / X2 ratio of at least 4, more particularly at least 8, e.g., a ratio of at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., at least 50, e.g., at least 60, e.g., at least 70, e.g., at least 80, e.g., at least 90, or e.g., at least 100, or e.g., at least 110, or e.g., at least 120, or e.g., at least 130, or e.g., at least 140, or e.g., at least 150, or e.g., at least 160, or e.g., at least 170, or e.g., at least 180, or e.g., at least 190, or e.g., at least 200.

[0117] In a specific embodiment, the zeolite comprises three interconnected non-parallel channel systems, wherein at least two of the interconnected non-parallel channel systems comprise channels with rings of more than 10 members; wherein the zeolite further comprises a framework Si / X2 ratio of at least 4, more particularly at least 8, for example a ratio of at least 10, for example a ratio of at least 15, for example a ratio of at least 20, for example a ratio of at least 25, for example a ratio of at least 30, for example a ratio of at least 35, for example a ratio of at least 40, for example a ratio of at least 50, for example a ratio of at least 60, for example a ratio of at least 70, for example a ratio of at least 80, for example a ratio of at least 90, or for example a ratio of at least 100, or for example a ratio of at least 110, or for example a ratio of at least 120, or for example a ratio of at least 130, or for example a ratio of at least 140, or for example a ratio of at least 150, or for example a ratio of at least 160, or for example at least 170, or for example a ratio of at least 180, or for example a ratio of at least 190, or for example a ratio of at least 200.

[0118] In most embodiments, the conversion of the sugar to be protected to a fully acetal-protected product increases with increasing Si / X2 ratio, preferably increases with increasing Si / X2 ratio. In some embodiments, it is observed that at higher Si / X2 ratios, the yield of partially protected sugar may decrease with further increase in the Si / X2 ratio. Without being bound by theory, it is believed that this is related to the lower number of acid sites but higher Bronsted acid strength in zeolites with high Si / X2 ratios. Thus, in a specific embodiment, the framework Si / X2 ratio of the zeolite is less than 280. In a further embodiment, the framework Si / X2 ratio of the zeolite is less than 150. Preferably, the framework Si / X2 ratio of the zeolite is less than 280. In a further embodiment, the framework Si / X2 ratio of the zeolite is less than 200.

[0119] The zeolite used in the processes described herein may include AlO4 tetrahedra, BO4 tetrahedra, or contain both. Thus, in some embodiments, X2 is (Al2 + B2). Thus, for a given zeolite, when Al in the framework is replaced by B, or vice versa B is replaced by Al, the Si / X2 framework ratio remains unchanged. However, it is contemplated that in a specific embodiment, the zeolite may not contain BO4 tetrahedra, or their content may be negligible (e.g., the Al / B ratio is more than 100). Thus, in a specific embodiment, X2 may be Al2.

[0120] Unless otherwise specified, the Si / X2 mentioned herein is the molar ratio determined by NMR. Those skilled in the art should understand that the Si / X2 ratio mentioned herein is equivalent to the SiO2 / X2O3 molar ratio, where X2O3 is (Al2O3 and / or B2O3). In addition, those skilled in the art will understand that the Si / X molar ratio is obtained by dividing the Si / X2 ratio by 2, where X is (Al and / or B).

[0121] Preferably, the channels defined by the zeolite topology are large enough to allow the saccharides to be protected to enter, but small enough to prevent the formation and / or diffusion of by-products in large quantities. Thus, in a specific embodiment, the zeolite contains channels with a ring size of at most 18, preferably at most 14, such as at most 12.

[0122] In a preferred embodiment, the zeolite suitable for the processes described herein has a topology selected from the group consisting of BEA, FAU, and MEL. These zeolites can produce a large amount of end products. In certain embodiments, the zeolite has a topology selected from the group consisting of MOR. In a specific embodiment, the zeolite contains a zeolite having a FAU or BEA topology, which can provide excellent results.

[0123] In certain embodiments, the zeolite contains channels with an average (equivalent) diameter of at least More specifically, the zeolite may contain five or more non-parallel channels with an average diameter of at least The channel diameter can be determined theoretically according to the knowledge of the zeolite framework type or measured by X-ray diffraction (XRD) as known to those skilled in the art. Preferably, the zeolite contains two or more non-parallel interconnected channels with an average (equivalent) diameter of to and more preferably from to Preferably, a suitable topological structure diameter can be obtained from international standard documents: as mentioned above, the Atlas of Zeolite structures or the corresponding online database, the website of which is http: / / www.iza-structure.org / databases / . The (equivalent) diameter of the channels can also be determined by N2 adsorption experiments, such as those discussed by Groen et al. (Microporous and Mesoporous Materials 2003, 60, 1-17), Storck et al. (Applied Catalysis A: General 1998, 174, 137-146) and Rouquerol et al. (Rouquerol F, Rouquerol J and Sing K, Adsorption by powders and porous solids: principles, methodology and applications, Academic Press, London, 1999).

[0124] In certain embodiments, the zeolite may further comprise mesopores. The presence of mesopores can increase the likelihood of the sugar to be protected entering the micropores, thereby further accelerating the reaction rate. However, it is also conceivable that the zeolite does not contain mesopores.

[0125] As used herein, the term "mesopore" refers to pores in zeolite crystals with an average diameter of 2.0 nm to 50 nm. For pore shapes deviating from cylindrical, the above mesopore diameter range refers to the equivalent cylindrical pores. The average mesopore diameter can be determined by gas adsorption techniques, such as N2 adsorption.

[0126] The zeolite can be used in the form of, for example, a powder. In certain embodiments, the zeolite can be mixed with other materials to formulate a catalyst, and these materials provide additional shape, hardness or catalytic activity to the finished catalyst. The materials that can be mixed with the zeolite can be various inert or catalytically active materials, or various binder materials. These materials include the following components: kaolin and other clays, phosphates, alumina or alumina sol, titanium dioxide, metal oxides such as zirconia, quartz, silica or silica sol, metal silicates and their mixtures. These components can effectively densify the catalyst and increase the strength of the formulated catalyst.

[0127] The catalyst can be formulated into granules, spheres, extruded into other shapes, or formed into spray-dried particles.

[0128] In some embodiments, the zeolite used in the methods described herein can be (post-synthetically) treated to increase the Si / X2 framework ratio. Methods for increasing the Si / Al2 ratio are known in the art and include dealuminating the framework by (hydro)thermal treatment, extracting framework aluminum with acid, and substituting framework aluminum with silicon by reaction with a silicon halide or hexafluorosilicate. Remy et al. describe exemplary dealumination methods (J. Phys. Chem. 1996, 100, 12440-12447). The zeolite used in the methods described herein is preferably a Bronsted acid zeolite, i.e., a zeolite having proton donor sites in the micropores. When all Al T sites are balanced by acidic protons (rather than cations), the Bronsted acid density can be directly derived from the Si / Al2 ratio, which is known to those skilled in the art.

[0129] The zeolite used in the processes described herein can be obtained in acidic form (acidic H-form zeolite) or (partially) ion-exchanged with cations other than H + In some embodiments, the acidic H-form zeolite can be used as is. In some other embodiments, the zeolite used in the processes described herein can be (post-synthetically) treated to increase the Bronsted acid density. The Bronsted acid sites in the zeolite can be readily generated by aqueous ion exchange with an ammonium salt followed by thermal decomposition of the ammonium ions inside the zeolite. Alternatively, acid sites can also be generated by aqueous ion exchange with a salt of a multivalent metal cation (such as Mg 2+ , Ca 2+ , La 3+ or mixed rare earth cations) followed by thermal dehydration (J. Weitkamp, Solid State Ionics 2000, 131, 175-188).

[0130] The zeolite catalysts described herein can be regenerated and reused in the processes. Accordingly, certain embodiments of the processes described herein can include a step of regenerating the zeolite catalyst. The regeneration of the zeolite catalyst can be carried out by washing or calcination. Preferably, the regeneration of the zeolite catalyst is carried out by calcination, for example, at a temperature of at least 150 °C. In a specific embodiment, the calcination temperature is at least 200 °C, such as at least 300 °C, such as at least 400 °C, such as at least 450 °C, such as about 550 °C.

[0131] The above zeolite can contain various dopants, such as but not limited to gallium, tin, or rare earth metals. The dopants can improve the stability of the catalyst or increase the conversion of sugars to obtain the desired fully or partially protected products.

[0132] Exemplary commercially available zeolites suitable for the processes described herein include, but are not limited to, beta-zeolite polymorph A (BEA topology), Y-zeolite (FAU topology), and mordenite.

[0133]

[0134] Preferably, the acidic zeolite catalyst is selected from the group consisting of: Y-zeolite (SiO2:Al2O3 = 5.2:1), Y-zeolite (SiO2:Al2O3 = 12:1), Y-zeolite (SiO2:Al2O3 = 30:1), Y-zeolite (SiO2:Al2O3 = 60:1), Y-zeolite (SiO2:Al2O3 = 80:1), beta-zeolite (SiO2:Al2O3 = 25:1), beta-zeolite (SiO2:Al2O3 = 38:1), beta-zeolite (SiO2:Al2O3 = 150:1), and mordenite (Modernite, SiO2:Al2O3 = 19:1).

[0135] Preferably, the aldehyde used in the process of the present invention can preferably be selected from the group consisting of: formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, hexanal, heptanal, octanal, nonanal, decanal, dodecanal, tetradecanal, hexadecanal, octadecanal, crotonaldehyde, glyoxal, malonaldehyde, succinaldehyde, glutaraldehyde, adipaldehyde, 2-hydroxyhexanedial, heptanedial, octanedial, nonanedial, decanedial, malealdehyde, fumaraldehyde, phthalaldehyde, isophthalaldehyde, terephthalaldehyde, and 1,4-diformylcyclohexane, glyoxylic acid, glyoxylic acid monohydrate, formylacetic acid, terephthalaldehyde, and succinic semialdehyde, preferably formaldehyde, acetaldehyde, dodecanal, glyoxylic acid, glyoxylic acid monohydrate, and glutaraldehyde.

[0136] Alternatively, the aldehyde source is selected from the group consisting of paraformaldehyde, 1,3,5-trioxane, polyoxymethylene, and paraldehyde. The polymeric or oligomeric compound forms the corresponding aldehyde under the reaction conditions.

[0137] Thus, the aldehyde can be a gas, a liquid, or a solid, and can exist in the form of a solution or a pure compound. For example, in the case of formaldehyde, it can be provided in the form of, for example, a gas, a formaldehyde solution (e.g., formalin), paraformaldehyde, or 1,3,5-trioxane, polyoxymethylene (POM).

[0138] In one embodiment of the present invention, R1 and R1', R2 and R2', R3 and R3' and R 12 and R 12 ' are the same. The compound can be obtained by using the same aldehyde, thus simplifying the synthesis scheme.

[0139] In another embodiment of the present invention, R1 and R1', R2 and R2', R3 and R3' and R 12 and R 12 ' are different from each other. For example, in the first step, the sugar to be protected is reacted with a first aldehyde (i.e., dodecyl aldehyde) in the presence of a heterogeneous acidic catalyst to protect one side of the sugar. Then, in the second step, this partially protected sugar is reacted with another aldehyde (such as glyoxylic acid) in the presence of a heterogeneous acidic catalyst to obtain a fully protected sugar.

[0140] In one embodiment of the present invention, the sugar to be protected is an aldose, thereby producing compounds of Formulas I, IV, V, IX, X, and XI,

[0141]

[0142]

[0143] wherein R1, R1', R4, R 5、 R 9、 R 10 and R 11 have the same definitions as described above.

[0144] Exemplary reactions for obtaining compounds of Formula I, IV, V, IX, X, or XI in the presence of a heterogeneous acidic catalyst are:

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] The pentose aldose can be selected from the group consisting of D-ribose, L-ribose, D-arabinose, L-arabinose, D-xylose, L-xylose, D-lyxose, and L-lyxose, most preferably D-arabinose and D-xylose, and ideally D-xylose. The stereochemical structure of the pentose aldose is known to those skilled in the art.

[0151] In one embodiment of the present invention, the sugar to be protected is a pentose aldose glycoside, and the partially protected sugar produced therefrom is selected from compounds of IVb, Xb, or XIb.

[0152]

[0153]

[0154] wherein R4, R 10 and R 11 are the same as defined above, and

[0155] R 13 、R 16 and R 17 are each independently hydrogen or a straight-chain, branched-chain or cyclic hydrocarbon moiety having 1 to 20 carbon atoms, preferably methyl, ethyl, propyl or butyl.

[0156] Exemplary reactions for obtaining compounds of formula IVb, Xb or XIb in the presence of a heterogeneous acidic catalyst are:

[0157]

[0158]

[0159]

[0160] In another embodiment of the present invention, the sugar to be protected is an aldohexose, whereby compounds of formula II, III, VIa, VII, VIIIa are produced

[0161]

[0162]

[0163] wherein R2, R2’, R3, R 3、 R 6、 R7 and R8 have the same definitions as above.

[0164] The aldohexose is preferably selected from the group consisting of D-allose, L-allose, D-altrose, L-altrose, D-glucose, L-glucose, D-mannose, L-mannose, D-gulose, L-gulose, D-idose, L-idose, D-galactose, L-galactose, D-talose and L-talose, most preferably D-glucose. The stereochemical structures of aldohexoses are known to those skilled in the art.

[0165] Exemplary reactions for obtaining compounds of formula II, III, VIa, VII and VIIIa in the presence of a heterogeneous acidic catalyst are:

[0166]

[0167]

[0168]

[0169]

[0170] In one embodiment of the present invention, the sugar to be protected is an aldohexoside, and the at least partially protected sugar thus produced is selected from the compounds of VIb, VIIIb, and XII:

[0171]

[0172]

[0173] wherein R6, R8, R 12 and R 12 ’ are as defined above, and

[0174] R 14 , R 15 and R 18 are each independently hydrogen or a straight-chain, branched-chain, or cyclic hydrocarbon moiety having 1 to 20 carbon atoms, preferably methyl, ethyl, or propyl.

[0175] Exemplary reactions for obtaining the compounds of VIb, VIIIb, and VII in the presence of a heterogeneous acidic catalyst are:

[0176]

[0177]

[0178]

[0179] Preferably, the catalyst has a pore structure such as the pore structure described in detail above for zeolites. The pore shape selectivity of the heterogeneous catalyst can tune the product selectivity and avoid the common problems in homogeneous catalyst systems, namely that the sugar molecule has many OH groups and a cyclic system, which easily form many by-products, so it is difficult to obtain high selectivity for a single desired product.

[0180] For compounds of formula I, II, III or XII, there is no restriction on the pore size, as long as the pore size allows the reactants to enter the Bronsted acid sites and allows the fully acetal-protected sugar to diffuse out. The pore size should also be large enough to allow the product to leave the catalyst after the reaction. If high selectivity for the partially protected sugar is preferred, the pore size should be larger than the desired partially protected sugar but smaller than the fully protected sugar. The specific pore size depends on the types of sugar and aldehyde used in the reaction. Those skilled in the art can predict the pore size ranges used in these cases. Due to steric hindrance, only unprotected or partially protected pentoses, pentosides, hexoses and hexosides can reach the catalytically active center through the pores and then leave the pores, so such catalysts can be used to prepare compounds of formula IV (IVa and IVb), V, VI (VIa and VIb), VII, VIII (VIIIa and VIIIb), IX, X (Xa and Xb) and XI (XIa and XIb). However, in order to obtain higher yields, for the protection of hexoses and hexosides, the pore size is preferably above 0.7 nm, and for the protection of pentoses and pentosides, the pore size is preferably above 0.5 nm, and the catalyst comprises mesopores with an average diameter of 2 nm to 50 nm.

[0181] In one embodiment of the present invention, the reaction is carried out in an organic solvent. Therefore, a sugar and an aldehyde or aldehyde source selected from the group consisting of pentoses, hexoses, pentosides and hexosides can react in a batch reactor or a continuous reactor, preferably a flow reactor, in the presence of the above-mentioned heterogeneous Bronsted acid catalyst and the organic solvent. The heterogeneous Bronsted acid catalyst used is preferably substantially insoluble in the organic solvent. After the reaction, if the catalyst is not confined within the reactor, such as in a basket or column packing, the catalyst can be removed by filtration or the like and then recycled and sent back to the reactor. The remaining reaction mixture can be concentrated by evaporating the solvent. The final product can be obtained by crystallization of the concentrate. Preferably, the organic solvent is selected from the group consisting of: dimethyl isosorbide, cyclic ethers, especially 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, sulfolane, sulfolene, fatty acids, especially acetic acid, alkylpyrrolidones, cyclic carbonates, cyclic esters, especially γ-valerolactone, γ-butyrolactone, acetonitrile, dialkyl ethers, especially CPME and diethyl ether, cyclic ethers, ethylene glycol monoethers and ethylene glycol diethers.

[0182] High conversion of the sugar can be ensured while removing the solvent. This solvent system is particularly preferred for long-chain aldehydes (such as decanal).

[0183] In another embodiment, the reaction is carried out in an aqueous solution. Thus, sugars selected from the group consisting of pentoses, hexoses, pentosides and hexosides and aldehydes or aldehyde sources can be reacted in a batch reactor or a continuous reactor, preferably a flow reactor, in the presence of the above-mentioned heterogeneous Bronsted acid catalyst and water. The heterogeneous Bronsted acid catalyst used is substantially insoluble in water. After the reaction, if the catalyst is not confined within the reactor, such as in a basket or column packing, the catalyst can be separated and recycled by filtration and / or centrifugation. The remaining liquid can be extracted with a solvent (such as hexane, DCM, ether, ethyl acetate or CPME) to remove the product. Then the extraction solvent can be removed by evaporation to separate the product. Alternatively, the product containing the extraction layer can be concentrated to cause the product to gradually crystallize in the concentrate. The extracted aqueous phase contains unreacted reactants, namely sugars, aldehydes and intermediates. The extracted aqueous phase can be concentrated and recycled to the reactor to improve the overall yield. For environmental reasons, using an aqueous solution as the solvent system is particularly preferred.

[0184] In one embodiment of the present invention, the reaction is carried out in a biphasic solvent system to achieve in-situ separation of the product from the reaction mixture and increase the product yield by shifting the reaction equilibrium. Specifically, the extraction phase is added to a batch reactor together with the reaction mixture and the heterogeneous acid catalyst. In a continuous flow reactor, the extractant can be added in a co-current, cross-current or counter-current manner. Preferably, the biphasic solvent system is selected from the group consisting of dialkyl ether / water (such as CPME / water, dialkyl ether / water), anisole / water, dialkyl ketone / water (such as methyl isobutyl ketone) and toluene / water, preferably CPME / water, toluene / water, most preferably CPME / water. The reaction takes place in the aqueous phase and the product is extracted into the organic layer during the reaction. For stability considerations, biphasic solvent systems selected from the group consisting of dialkyl ether / water and dialkyl ketone / water are more suitable for aldehydes without side chains or with short side chains, such as formaldehyde and acetaldehyde. The product phase containing the extractant is concentrated to crystallize the product. The remaining product in the aqueous phase can be further extracted with a solvent (such as ethyl acetate or CPME) to remove the product that can also crystallize after evaporation of the extraction solvent. The extracted aqueous phase can be concentrated and recycled as described above.

[0185] The reaction temperature is preferably from 50 °C to 160 °C, most preferably from 80 °C to 140 °C. In an organic solvent, the reaction temperature is usually from 80 to 130 °C; in a biphasic solvent system, the reaction temperature is usually from 120 to 140 °C; in an aqueous solution, the reaction temperature is preferably between 120 and 150 °C. The reaction time is determined by the degree of conversion achieved.

[0186] The amount of the heterogeneous acid catalyst depends on the amount of sugar to be protected. For an alternative preferred continuous operation mode, the relative amount of the catalyst will be adjusted according to the size of the reactor and the flow rate of the pentose or hexose. In this case, it should be understood that determining the appropriate relative amount based on data from the batch operation mode is within the normal skill of a production chemist or chemical engineer.

[0187] The method of the present invention can be conveniently carried out under normal ambient conditions, but can also be carried out under an inert gas environment, preferably under a gaseous nitrogen, helium or argon environment. Examples

[0188] The following Examples 1 to 5 are based on the production of DFX using formaldehyde. The same principle can also be applied to other aldehydes to produce different types of fully or partially protected xyloses, especially dipropyl xylose, di-n-butyl xylose, diisobutyl xylose, didodecyl xylose, etc.

[0189] Example 1:

[0190] D-Xylose (2 g, 13.3 mmol, 1.0 equivalent), paraformaldehyde (2 g, 66.7 mmol formaldehyde, 5.0 equivalents) and H-form Y zeolite (SiO2:Al2O3 = 80:1, 2 g) were added to 2-Me-THF (32 mL) in a 50 mL round-bottom flask. The mixture was then heated to 120 °C and stirred for 6 hours. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and concentrated in vacuo using a rotary evaporator in a 45 °C water bath. HPLC determination showed that the DFX yield of D-xylose was 82.3%. The concentrated residue was crystallized at 4 °C to 5 °C.

[0191] The same method can also use other catalysts. Table 1 shows the different DFX yields using different catalysts. All these reactions were carried out using 0.25 g of D-xylose, and all other chemical reagents were scaled down according to the ratio of the above example. The reactions were carried out in a 10 mL glass reaction kettle.

[0192] Table 1. DFX yields and xylose conversions using different heterogeneous catalysts and reaction times with paraformaldehyde as the formaldehyde source

[0193]

[0194] Example 2:

[0195] D-Xylose (0.1 g, 0.67 mmol, 1.0 equivalent), paraformaldehyde (0.1 g, 3.34 mmol, 5 equivalents) and ZrO2 / SO4 2-(Self-synthesized, 50 mg) was added to 2-Me-THF (2 mL) in a 10 mL glass reactor. The mixture was then heated to 110 °C and stirred for 9 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and diluted 10-fold with distilled water. HPLC determination showed a DFX yield of 79% for D-xylose.

[0196] The same method can also be used with other acidic catalyst sets (e.g., Amberlite, sulfated ZrO2, heteropolyacids, niobium oxides) (Table 2).

[0197] Table 2. DFX yields and xylose conversions using different heterogeneous catalysts and reaction times with paraformaldehyde as the formaldehyde source

[0198]

[0199] Example 3:

[0200] D-Xylose (0.1 g, 0.67 mmol, 1.0 equiv), 37% aqueous formalin (0.5 ml, 10.3 equiv), and β-zeolite (SiO2:Al2O3 = 25:1, 0.1 g) were added to GVL (5 mL) in a 10 mL glass reactor. The mixture was then heated to 140 °C and stirred for 2 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and distilled under reduced pressure (10 mbar) at 80 °C to remove GVL. HPLC determination showed a DFX yield of 76% for D-xylose. The concentrated residue was crystallized at 4 °C to 5 °C.

[0201] The same method can also be used with other catalysts and solvents. Table 3 shows the different DFX yields using other catalysts.

[0202] Table 3. DFX yields and xylose conversions using various heterogeneous catalysts and reaction times with formalin (aqueous formaldehyde) as the formaldehyde source

[0203]

[0204] Example 4:

[0205] D-xylose (8 g, 53.3 mmol, 1.0 equiv), 37% aqueous formalin solution (40 mL, 10.3 equiv), and Y-type zeolite (SiO₂:Al₂O₃ = 80:1, 1.6 g) were mixed in a 60 mL glass reactor. The mixture was then heated to 140 °C and stirred for 6 h. HPLC measurement showed that the DFX yield from D-xylose was 57.6%. The resulting solution was cooled to room temperature (ca. 23 - 25 °C) and filtered through a nylon membrane filter. The filtrate was extracted four times with 10 mL of ethyl acetate or cyclopentyl methyl ether in a separating funnel. The resulting organic layer was concentrated under reduced pressure (0.02 mbar) at 45 °C to obtain a DFX-rich liquid. Then, DFX in the liquid was crystallized at 4 - 5 °C or room temperature.

[0206] The same method can also use other catalysts. Table 4 shows the different DFX yields using other catalysts.

[0207] Table 4. DFX Yields and Xylose Conversions Using Example 4 with Different Heterogeneous Catalysts and Reaction Times

[0208]

[0209] Example 5:

[0210] D-xylose (0.3 g, 2 mmol, 1.0 equiv), 37 wt% aqueous formalin solution (1.5 mL, 10.3 equiv), and Y-type zeolite (SiO₂:Al₂O₃ = 80:1, 0.2 g) were mixed in a 10 mL glass reactor. Cyclopentyl methyl ether (4.5 mL, 3 vol. equiv) was added to the aqueous layer. The mixture was then heated to 140 °C and stirred for 4 h. HPLC measurement showed that the DFX yield in the organic cyclopentyl methyl ether layer was 50.4% and that in the aqueous layer was 18.4%. The solution was cooled to room temperature (ca. 23 °C to 25 °C). The aqueous layer and the organic layer were separated and filtered through a nylon membrane filter. The organic layer was distilled under reduced pressure (0.02 mbar) at 45 °C to obtain a concentrated solution. The aqueous filtrate was extracted three times with 1.5 mL of ethyl acetate or cyclopentyl methyl ether in a separating funnel. The extracted layer was distilled under reduced pressure (0.02 mbar) at 45 °C to obtain a concentrated solution. The two concentrated solutions were combined and then crystallized at 4 - 5 °C to obtain white crystalline DFX.

[0211] Other extraction solvents such as anisole, methyl isobutyl ketone, dibutyl ether, and toluene can also be used in the same method with different addition amounts (Table 5).

[0212] Table 5. DFX Yields and Xylose Conversions Using Example 5 with Different Heterogeneous Catalysts and Reaction Times

[0213]

[0214] Example 6:

[0215] D-Xylose (0.25 g, 1.67 mmol, 1.0 equiv), dodecyl aldehyde (0.75 mL, 2 equiv), and Y zeolite (SiO2:Al2O3 = 30:1, 0.1 g) were added to dioxane (5 mL) in a 10 mL glass reactor. The mixture was then heated to 65 °C and stirred for 5 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and the dioxane was removed using a rotary evaporator in a 45 °C water bath. GC-FID measurement showed that the yield of MDX (3,5-O-didodecylidene-xylose) from D-xylose was 66.2%, the yield of MDX (1,2-O-didodecylidene-xylose) was 7.2%, and the yield of DDX (didodecylidene-xylose) was 3.9%. The following table summarizes the similar reactions using other heterogeneous catalysts (yields of MDX and DDX and xylose conversion using various heterogeneous catalysts in Example 6).

[0216]

[0217] Example 7:

[0218] Glyoxylic acid monohydrate (0.29 g, 2 equiv) was added to 1,4-dioxane (5 mL). The mixture was pre-dried with 0.6 g of 4A molecular sieve to remove moisture. MDX (0.5 g, 1.6 mmol, 1 equiv, isolated from Example 6) was added to the dried mixture in a 10 mL glass reactor together with Amberlyst 15 (0.125 g). The mixture was then heated to 80 °C and stirred for 4 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and the dioxane was removed using a rotary evaporator in a 45 °C water bath. GC-FID measurement showed that the yield of GMAX (1,2-O-glyoxylic acid-3,5-O-didodecylidene-xylose) was 59.4%.

[0219] Example 8:

[0220] D - xylose (5.0 g, 33 mmol, 1.0 equiv), glyoxylic acid monohydrate (7.66 g, 2.5 equiv), and sulfonated resin (Dowex r 50wx8, hydrogen form, 200 - 400 mesh, 1.5 g) were added to sulfolane (20 mL) in a 100 mL round - bottom flask. The mixture was heated to 90 °C under reduced pressure (40 mbar) for 5 h while stirring by rotating the flask. The resulting solution was cooled to room temperature (ca. 23 - 25 °C), filtered through a nylon membrane filter to remove the Dowex catalyst. The yield of di - glyoxylate xylose (DGAX) was 77% based on the xylose loading as measured by HPLC.

[0221] Example 9:

[0222] D - xylose (0.25 g, 1.67 mmol, 1.0 equiv), various aldehydes (2 equiv), and zeolite Y (SiO2:Al2O3 = 80:1, 0.25 g) were added to 1,4 - dioxane (5 mL) in a 10 mL glass reactor. The mixture was then heated to 65 °C and stirred for 5 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and the dioxane was removed using a rotary evaporator in a 45 °C water bath.

[0223] For comparison, D - xylose (0.25 g, 1.67 mmol, 1.0 equiv), various aldehydes (2 equiv), and H2SO4 (5.3 μL) were added to dioxane (5 mL) in a 10 mL glass reactor. The mixture was then heated to 65 °C and stirred for 5 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and the dioxane was removed using a rotary evaporator in a 45 °C water bath.

[0224] The yields of various products from each aldehyde heterogeneous and homogeneous reactions were paired - compared by GC - FID measurement in the following table (the yields of products IVa, Va, Xa, XIa, and I and the xylose conversion using various aldehydes in Example 9).

[0225]

[0226] Example 10:

[0227] L - arabinose (0.25 g, 1.67 mmol, 1.0 equiv), dodecyl aldehyde (0.75 ml, 2 equiv), and Y - type zeolite (SiO₂:Al₂O₃ = 30:1, 0.25 g) were added to 1,4 - dioxane (5 ml) in a 10 mL glass reactor. The mixture was then heated to 65 °C and stirred for 5 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and 1,4 - dioxane was removed using a rotary evaporator in a 45 °C water bath. GC - FID measurement showed that 77.3% of partially protected arabinose and 12.7% of fully protected arabinose were obtained.

[0228] Example 11:

[0229] D - glucose (0.3 g, 1.67 mmol, 1.0 equiv), dodecyl aldehyde (1.85 ml, 5 equiv), and Y - type zeolite (SiO₂:Al₂O₃ = 30:1, 0.25 g) were added to 1,4 - dioxane (5 ml) in a 10 mL glass reactor. The mixture was then heated to 80 °C and stirred for 5 h. The resulting solution was cooled to room temperature (∼23 °C to 25 °C), filtered through a nylon membrane filter, and 1,4 - dioxane was removed using a rotary evaporator in a 45 °C water bath. GC - FID measurement showed that the yield of partially protected glucose was 58.0% and the yield of fully protected glucose was 34.3%.

Claims

1. A method for preparing at least partially acetal - protected sugars, comprising the following steps: React a sugar or sugar derivative selected from the group consisting of pentoses, hexoses, pentosides, and hexosides with an aldehyde or aldehyde source in the presence of a heterogeneous acid catalyst to form at least a portion of the acetal-protected sugar selected from the group consisting of compounds of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII. Among them, R1, R1’, R2, R2’, R3, R3’, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 12 ’ are Y or Z-E, where R1 and R1’, R2 and R2’, R3 and R3’, R 12 and R 12 ’ are the same as or different from each other, and Y is hydrogen or a straight-chain, branched, or cyclic hydrocarbon moiety having from 1 to 20 carbon atoms. Z is a straight-chain, branched, or cyclic hydrocarbon moiety having from 0 to 12 carbon atoms, optionally substituted with 1 to 4 C1-C4 alkyl groups, 1 to 4 halogen atoms, or benzyl, and E is -COOH, -CH(COOH)2, -COOR 19 , -CH(COOR 20 )(COOR 21 ), -CHO, -CH(CHO)2, -C2H3, CH(C2H3)2, -CHCHR 22 , -CHCR 23 R 24 , -C2H, -C2R 25 , -N3, -NH2, -CH(NH2)2, -NHR 26 , -CH(NHR 27 )(NHR 28 ), -NR 29 R 30 , -CH(NR 31 R 32 )(NR 33 R 34 ), -OH, -OR 35 , -CH(R 36 OH)(R 37 OH), and R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 and R 35 each independently is C1 to C 20 alkyl, and R 20 and R 21 、R 23 and R 24 、R 27 and R 28 、R 29 and R 30 、R 31 and R 32 、as well as R 33 and R 34 are the same as or different from each other, and R 36 and R 37 each independently is "absent", or a straight-chain or branched C1 to C 12 hydrocarbon chain, and R 13 、R 14 、R 15 、R 16 、R 17 and R 18 each independently is hydrogen or a straight-chain, branched-chain or cyclic hydrocarbon moiety having 1 to 20 carbon atoms.

2. The method according to claim 1, wherein, the heterogeneous acid catalyst is a Bronsted acid catalyst, preferably selected from the group consisting of: a. Acidic zeolites, b. Acid-doped zeolites, c. Acid-site functionalized resins, d. Acid-site functionalized oxides, e. Acidic oxides, f. Heteropolyacids and their derivatives.

3. The method according to claim 2, wherein, The heterogeneous Bronsted acid catalyst is an acidic zeolite, preferably comprising: - at least two, preferably two or three, non-connected parallel channel systems, wherein at least one of said channel systems comprises channels with rings of 8 members or more; and the framework Si / X2 ratio measured by NMR is at least 4; or - at least two, preferably two or three, interconnected non-parallel channel systems, wherein at least one of said channel systems comprises channels with rings of 10 members or more; and the framework Si / X2 ratio measured by NMR is at least 4; or - three interconnected non-parallel channel systems, wherein at least two of said channel systems comprise channels with rings of 10 members or more, and the framework Si / X2 ratio measured by NMR is at least 4, wherein each X is Al or B.

4. The method according to any one of the preceding claims, wherein, The aldehyde is selected from the group consisting of formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, hexanal, heptanal, octanal, nonanal, decanal, dodecanal, tetradecanal, hexadecanal, octadecanal, crotonaldehyde, glyoxal, malonaldehyde, succinaldehyde, glutaraldehyde, adipaldehyde, 2-hydroxyadipaldehyde, pimelaldehyde, suberaldehyde, azelaic aldehyde, sebacic aldehyde, malealdehyde, fumaraldehyde, phthalaldehyde, isophthalaldehyde, terephthalaldehyde, and 1,4-diformylcyclohexane, glyoxylic acid, glyoxylic acid monohydrate, formylacetic acid, and succinic semialdehyde, preferably formaldehyde, acetaldehyde, dodecanal, glyoxylic acid, glyoxylic acid monohydrate, and glutaraldehyde.

5. The method according to any one of claims 1 to 3, wherein, The aldehyde source is selected from the group consisting of paraformaldehyde, 1,3,5-trioxane, polyoxymethylene, and paraldehyde.

6. The method according to any one of the preceding claims, wherein, R 13 、R 14 、R 15 、R 16 、R 17 and R 18 are hydrogen, methyl or ethyl, preferably hydrogen.

7. The method according to any one of the preceding claims, wherein, The sugar is a pentose.

8. The method according to any one of the preceding claims, wherein, The sugar is arabinose or xylose, preferably D-xylose.

9. The method according to any one of claims 1 to 6, wherein, The sugar is glucose, preferably D-glucose.

10. The method according to any one of the preceding claims, wherein, The catalyst has a pore structure.

11. The method according to any one of the preceding claims, wherein, The reaction is carried out in an organic solvent, which is preferably selected from the group consisting of dimethyl isosorbide, cyclic ethers, especially 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, sulfolane, vinyl sulfone, fatty acids, especially acetic acid, alkyl pyrrolidones, cyclic carbonates, cyclic esters, especially γ-valerolactone, γ-butyrolactone, acetonitrile, dialkyl ethers, especially diethyl ether, cyclic ethers, especially CPME and diethyl ether, cyclic ethers, ethylene glycol monoethers and ethylene glycol diethers.

12. The method according to any one of claims 1 to 10, wherein, The reaction is carried out in an aqueous solution.

13. The method according to any one of claims 1 to 10, wherein, The reaction is carried out in a biphasic solvent system, which is preferably selected from the group consisting of CPME / water, anisole / water, dialkyl ether / water, dialkyl ketone / water and toluene / water, preferably CPME / water and toluene / water, most preferably CPME / water.

14. The method according to any one of the preceding claims, wherein, The reaction is carried out at a temperature of 50 °C to 160 °C, preferably 80 °C to 140 °C.

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