Preparation of 2,3,5-trimethylhydroquinone from a mixture of mesitol and 2,3,6-trimethylphenol

Abstract

The present invention relates to a process for producing 2,3,5-trimethylhydroquinone from a mixture of mesitol and 2,3,6-trimethylphenol (=2,3,6-TMP), which provides a highly attractive and commercially interesting method for producing α-tocopherol.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of producing 2,3,5-trimethylhydroquinone and α-tocopherol.

[0002] [Background of the invention] 2,3,5-Trimethylhydroquinone (TMHQ) is an important substance in the synthesis of α-tocopherol. It is typically produced from m-cresol, followed by methylation to give 2,3,6-trimethylphenol, which is oxidized to give trimethylquinone (TMQ), which is then reduced to give TMHQ. This is disclosed, for example, by W. Bonrath et al. Angew. Chem. Int. Ed. 2012, 51, 12982-12985 or Bonrath, W. et al. (2021). Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). In Ullmann's Encyclopedia of Industrial Chemistry. https: / / doi.org / 10.1002 / 14356007.o27_o07.pub2.

[0003] Traditionally, cresols can be extracted from coal tar. However, this results in a mixture of the isomers o-cresol, m-cresol, and p-cresol. While o-cresol is easily separated from this mixture, m-cresol is very difficult to isolate from the residual mixture of m-cresol and p-cresol. Therefore, in the current industrial production of TMHQ, m-cresol is supplied by other synthetic routes, particularly to the m-isomer. However, these processes are very complex and expensive, significantly affecting the price of m-cresol suitable for this process.

[0004] In view of the growing awareness of the sustainability of chemical processes, there has been a significant increase in interest in using raw materials derived from natural resources.

[0005] WO 2015 / 110654A1 and WO 2015 / 110655A1 disclose that 2,5-dimethylphenol or 2,3,6-trimethylphenol can be obtained from 2,5-dimethylfuran and ethyne or propyne, respectively, in the presence of an Au(I) complex. However, these procedures result in an isomeric mixture of phenols. In particular, in the case of ethyne, a significant amount of 2,4-dimethylphenol is known to be produced as a by-product in the synthesis of the targeted 2,5-dimethylphenol.

[0006] A new oxidation method for obtaining TMHQ has recently been discovered. WO 2021 / 234077 A1 discloses that 2,3,5-trimethylphenol can be photooxidized to 2,3,5-trimethylbenzoquinone.

[0007] WO 2022 / 128852 A1 discloses that 2,4,6-trimethylphenol can be photooxidized to 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, which can be converted to 2,3,5-trimethylhydroquinone.

[0008] All these state-of-the-art documents have in common that their respective syntheses start from a particular isomer of dimethylphenol or trimethylphenol.

[0009] Swiss Patent No. 576928 discloses a process for TMHQ that starts with a mixture of 2,3,6- and 2,4,6-trimethylphenol and uses sulfonation and separation of the desired isomer from the undesired isomers. However, this process is highly disadvantageous because only one isomer of trimethylphenol (2,3,6) from the isomeric mixture is used to synthesize the desired 2,3,5-trimethylhydroquinone, while the other isomer (2,4,6-TMP), which is present in a significant amount (24%), is waste.

[0010] [Summary of the Invention] Surprisingly, it has been found that the process according to claim 1 can be used to form 2,3,5-trimethylhydroquinone from a mixture of 2,4,6-trimethylphenol and 2,3,6-trimethylphenol.

[0011] This provides a novel route using a raw material that is a mixture of isomers of phenols. It is not necessary to separate the isomers using very expensive separation techniques or to use complex and expensive synthetic routes that result in only one isomer specific to the starting material. It has been specifically found that TMHQ can be obtained in very high yield and selectivity using a mixture of m- and p-cresol. Furthermore, the present invention enhances the attractiveness of using 2,5-dimethylfuran as a sustainable starting material for the synthesis of TMHQ.

[0012] The present process is highly advantageous in that it can convert both the 2,4,6-trimethylphenol and 2,3,6-trimethylphenol isomers into the desired 2,3,5-trimethylhydroquinone.

[0013] Further aspects of the invention are the subject matter of further independent claims. Particularly preferred embodiments are the subject matter of the dependent claims. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows schematic diagrams of different preferred synthetic routes for the process of producing 2,3,5-trimethylhydroquinone of formula (I) from a mixture of mesitol (formula IIa) and 2,3,6-TMP (formula IIb). [Figure 2] Different preferred synthetic routes to obtain a mixture of mesitol (Formula IIa) and 2,3,6-TMP (Formula IIb) are outlined below. [Figure 3] 1 shows a schematic diagram of the preparation of alpha-tocopherol (formula (VIII)) from 2,3,5-trimethylhydroquinone of formula (I).

[0015] [Detailed Description of the Invention] In a first aspect, the present invention relates to a process for producing 2,3,5-trimethylhydroquinone (TMHQ) of formula (I) from a mixture of mesitol (=2,4,6-trimethylphenol = 2,4,6-TMP) of formula (IIa) and 2,3,6-trimethylphenol (=2,3,6-TMP) of formula (IIb). [ka]

[0016] The process involves the following successive steps: a) providing a mixture of a compound of formula (IIa) and a compound of formula (IIb); [ka] b) oxidizing the mixture of compounds of formula (IIa) and formula (IIb) to form a mixture of compounds of formula (IIIa) and formula (IIIb); [ka] c) reducing the mixture of the compound of formula (IIIa) and the compound of formula (IIIb) with a reducing agent to obtain a mixture of the compound of formula (IV) and the compound of formula (I); [ka] d) treating a mixture of the compound of formula (IV) and the compound of formula (I) with a basic substance at a temperature above 200°C, preferably above 240°C, to rearrange the compound of formula (IV) in the mixture to give the compound of formula (I) [ka] The method includes the step of obtaining:

[0017] In this specification, "C x~yAn "alkyl" group is an alkyl group containing x to y carbon atoms, i.e., for example, C 1~3 An alkyl group is an alkyl group containing 1 to 3 carbon atoms. An alkyl group can be straight or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4 alkyl group.

[0018] Similarly, C x~y Alkanol, or C x~y An alkylenediol is an alcohol having one or two OH groups, where the alcohol has an alkyl or alkylene group containing x to y carbon atoms.

[0019] The term "independently of each other" as used herein in reference to substituents, moieties or groups means that identically designated substituents, moieties or groups can exist simultaneously in the same molecule with different meanings.

[0020] In this specification, when the same symbol appears for a symbol or group in several formulas, the definition of said group or symbol given in relation to one particular formula also applies to other formulas containing the same symbol.

[0021] As used herein, the term "inert" when describing a material means that said material does not undergo any chemical reaction under the reaction conditions.

[0022] The peak wavelength is the wavelength at which the spectrum reaches its maximum intensity.

[0023] [Providing a mixture of mesitol (formula (IIa)) and 2,3,6-TMP (formula (IIb))] [(Step a))] In step a), a mixture of a compound of formula (IIa) (mesitol (=2,4,6-trimethylphenol = 2,4,6-TMP)) and a compound of formula (IIb) (2,3,6-trimethylphenol (=2,3,6-TMP)) is provided. [ka]

[0024] In a first preferred embodiment, said mixture is provided by methylation step a'') of a mixture of m-cresol and p-cresol to a mixture of mesitol and 2,3,6-TMP.

[0025] Thus, a mixture of compound (IIa) and compound of formula (IIb) is subjected to reaction step a″). a'') Methylation of a mixture of p-cresol of formula (0p) and m-cresol of formula (0m) [ka] which preferably results in a mixture of compounds of formula (IIa) and formula (IIb).

[0026] The methylation in step a'') can be carried out by various methods.

[0027] In a preferred manner, a mixture of p-cresol and m-cresol is methylated in the presence of lithium hydroxide monohydrate at elevated temperatures, e.g., with methanol in an autoclave, to give a mixture of mesitol and 2,4,6-TMP, as disclosed in EP 1 108 705 A1, particularly in Example 3. The disclosure of the above-mentioned EP patent is incorporated herein in its entirety by reference.

[0028] In an even more preferred mode, the methylation of a mixture of p-cresol and m-cresol is carried out by vapor phase methylation, in particular by subjecting the mixture of p-cresol and m-cresol to a mixture of methanol and, optionally, water, in an inert atmosphere in the presence of an oxidation catalyst at a temperature of 300-500° C. This process produces little waste and allows for a continuous process, thus offering significant economic and ecological advantages.

[0029] In a second, more preferred embodiment, the mixture of mesitol and 2,3,6-TMP is provided by methylation step a') of a mixture of 2,4-dimethylphenol (=2,4-DMP, formula (IIa-1H)) and 2,5-dimethylphenol (=2,5-DMP, formula (IIb-H)). [ka]

[0030] The methylation in step a') can be carried out by various methods.

[0031] In a preferred manner, a mixture of 2,4-DMP and 2,5-DMP is methylated in the presence of lithium hydroxide monohydrate at elevated temperatures, e.g., with methanol in an autoclave, to give a mixture of mesitol and 2,4,6-TMP, as disclosed in EP 1 108 705 A1, particularly in Example 3. The disclosure of the above-mentioned EP patent is incorporated herein in its entirety by reference.

[0032] In an even more preferred manner, the methylation of a mixture of 2,4-DMP and 2,5-DMP is carried out by vapor phase methylation, in particular by exposing the mixture of 2,4-DMP and 2,5-DMP to a mixture of methanol and optionally water in an inert atmosphere in the presence of an oxidation catalyst at a temperature of 300 to 500°C, to give a mixture of mesitol and 2,4,6-TMP.

[0033] The main advantages of the gas phase methylation process are the high selectivity, which leads to reduced waste formation and a continuous process. The use of this process leads to particularly high economic and ecological advantages.

[0034] A mixture of 2,4-DMP (formula (IIa-1H)) and 2,5-DMP (formula (IIb-H)) can be obtained from the reaction of a compound of formula (V) and ethyne in the presence of a Pt or Au catalyst, either in the form of a salt or complex. [ka]

[0035] In a third preferred embodiment, a mixture of mesitol and 2,3,6-TMP is obtained from the reaction of a compound of formula (V) and propyne in the presence of a Pt or Au catalyst, either in the form of a salt or complex.

[0036] Therefore, in a highly preferred embodiment, the mixture of compound (IIa) and compound of formula (IIb) is subjected to reaction step a0) a0) reacting a compound of formula (V) with a compound of formula (VI) in the presence of a Pt or Au catalyst, either in the form of a salt or complex [ka] (wherein R represents H or CH3, preferably CH3); Formula (IIa-1) and Formula (II-b) [ka] with the proviso that when R represents H, the mixture of compounds of formula (IIa-1H) and formula (IIb-1H) is obtained by reaction step a') [ka] a') methylating the mixture of formula (IIa-1H) and formula (IIb-1H) to obtain a mixture of compounds of formula (IIa) and formula (IIb). [ka]

[0037] 2,5-Dimethylfuran is reacted with propyne (R=CH3) or acetylene (R=H). Both propyne and acetylene are gases.

[0038] When R represents CH3, propyne can also be mixed with propadiene. Certain mixtures containing propyne and propadiene are known to those skilled in the art as MAF gas (MAF = methylacetylene-arene fraction). MaF gas is an inexpensive process gas and is commercially available from various suppliers.

[0039] In one embodiment, step a0) is carried out in the presence of a gold catalyst.

[0040] This is described in detail in WO 2015 / 110655 A1 (using ethyne) or WO 2015 / 110654 A1 (using propyne), the entire disclosures of which are incorporated herein by reference.

[0041] In another embodiment, step a0) is carried out in the presence of a platinum catalyst.

[0042] The platinum catalyst is preferably in the form of either a platinum salt or a platinum complex.

[0043] In one embodiment, the platinum catalyst is preferably a Pt(II) salt, especially PtCl2.

[0044] In another embodiment, the platinum catalyst is preferably a complex of Pt(II), in particular a complex of Pt(II) with at least one organic ligand comprising at least one phosphorus atom, in particular a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.

[0045] Particularly preferred as a Pt catalyst is PtCl2 in the presence of an organic ligand containing at least one phosphorus atom, especially a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.

[0046] The organic ligand is preferably triphenyl phosphite (P(OPh)), diphenyl phosphate ((PhO)P=O(OH)), triphenyl phosphate ((PhO)P=O), triethyl phosphate ((EtO)P=O), dibenzyl phosphite ((PhCHO)P=O(H)), methyl diphenyl phosphite ((MeO)P(OPh)), triphenylphosphine (P(Ph), P(Ph 5F )3, bis-(2,2,2-trifluoroethyl)-phosphite ((CF3CH2O)2P=O(H)), triethyl 2-fluoro-2-phosphonoacetate ((CHFCOOEt)(EtO)2P=O), tris(2-tolyl)phosphite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphonopropionate) ((CH2CH2COOEt)(EtO)2P=O), 2-(diphenylphosphino)benzoic acid (P(Ph)2C6H4COOH), 3,9-bis(2,4-di-tert-butylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane (Ultranox 626), P(O-isooctyl)3), P(O-isopropyl)3), P(Oi-PrF6), P(On-Bu), bis(2,4-di-tert-butylphenoxy)-λ2-phosphane, CH3P(EtO)2, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (= 4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide), VAPOL hydrogen phosphate (= 18-hydroxy-8,9-diphenyldiphenanthro[4,3-d:3',4'-f][1,3,2]dioxaphosphepine 18-oxide), methyltriphenoxyphosphonium iodide ([CH3P(OPh)3] + I -, 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane ((CH2CH2COOEt)(EtO)2P=O, trimethylolpropane phosphite), trisodium triphenylphosphine trisulfonate (=TPPTS), disodium triphenylphosphine disulfonate (=TPPDS) and sodium triphenylphosphine monosulfonate (=TPPMS); In the formula, Ph represents phenyl, Ph 5F represents pentafluorophenyl, Et represents ethyl, and Me represents methyl.

[0047] The organic ligand is more preferably triphenyl phosphite (P(OPh)), diphenyl phosphate ((PhO)P=O(OH)), dibenzyl phosphite ((PhCHO)P=O(H)), triphenyl phosphate ((PhO)P=O), methyl diphenyl phosphite ((MeO)P(OPh)), trisodium triphenylphosphine trisulfonate (=TPPTS), P(Ph 5F )3, bis-(2,2,2-trifluoroethyl)-phosphite ((CF3CHO)2P=O(H)), tris(2-tolyl)phosphite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphonopropionate) ((CH2CH2COOEt)(EtO)2P=O), 2-(diphenylphosphino)benzoic acid (P(Ph)2C6H4COOH), and 9-bis(2,4-di-tert-butylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane (Ultranox 626); where Ph represents phenyl and Ph 5F represents pentafluorophenyl, Et represents ethyl, and Me represents methyl.

[0048] The reaction of 2,5-dimethylfuran with propyne or acetylene is preferably carried out in the presence of an ether or ketone, in particular a cyclic ether, preferably tetrahydrofuran, or acetone or methyl ethyl ketone or diethyl ketone, preferably acetone.

[0049] The amount of Pt catalyst is more preferably in the range of 0.1 to 25 mol %, particularly preferably 6 to 12 mol %, relative to the compound of formula (V).

[0050] The molar ratio of the organic ligand containing at least one phosphorus atom to Pt is more preferably in the range of 1 to 2, preferably 0.5 to 1.5, and more preferably 0.4 to 1.2.

[0051] The molar ratio of the compound of formula (V) to the compound of formula (VI) is preferably in the range of 1:1 to 1:8, in particular in the range of 1:1 to 1:8, preferably in the range of 1:1 to 1:3.

[0052] The reaction is more preferably carried out at a temperature of 0°C to 80°C, particularly 10°C to 60°C, and preferably 20°C to 30°C.

[0053] At temperatures above the boiling point of the solvent, the reaction is preferably carried out under pressure.

[0054] The above process produces a mixture of compounds of formula (IIa) and (IIb), or compounds of formula (IIa-1H) and (IIb-1H), respectively.

[0055] When R is H, the formation of 2,4-DMP (IIa-1H) is predominant. Typically, the molar ratio of 2,4-DMP:2,5-DMP is greater than 50:50.

[0056] As in the present process, 2,4-DMP having a methyl group para to the phenolic OH group in 2,4-DMP can also be used to produce the desired 2,3,5TMHQ, and the formation of a high content in 2,5-DMP is not disadvantageous.

[0057] The molar ratio of the compound of formula (IIa-1H) (= 2,4-dimethylphenol = 2,4-DMP) to the compound of formula (IIb-1H) (= 2,5-dimethylphenol = 2,5-DMP) is typically <70:30, in particular <60:40, preferably <50:50.

[0058] When R is CH3, the molar ratio of the compound of formula (IIa) to the compound of formula (IIb) is i≦50:50, in particular <10:90, more in particular <5:95, preferably <3:97, more preferably <2:98.

[0059] [Oxidation (step b))] In step b), the mixture of compounds of mesitol (formula (IIa)) and 2,3,6-TMP (formula (IIb)) is oxidized to form a mixture of compounds of formula (IIIa) and formula (IIIb) provided. [ka]

[0060] In one embodiment, the oxidation of step b) is a classical chemical oxidation, which can be carried out by methods primarily known to those skilled in the art.

[0061] In particular, this can be carried out with molecular oxygen, in particular in the presence of cobalt complexes and / or in the presence of a base, in particular an alkali metal salt, as disclosed in detail in DE 2314600 or DE 2747497.

[0062] Additionally, the oxidation in step b) can be carried out with chlorine in a suitable solvent, preferably in the absence of a base, followed by hydrolysis with water as described in U.S. Pat. No. 4,612,401, which is incorporated herein by reference.

[0063] Furthermore, the oxidation in step b) can be carried out with a hypohalogen acid or salt in an aqueous medium or a mixture of water and an organic solvent, as disclosed in detail in EP 0 084 158 A1, the entire disclosure of which is incorporated herein by reference.

[0064] In another more preferred embodiment, the oxidation in step b) is a photochemical oxidation.

[0065] The oxidation step b) comprises the step of reacting oxygen and a compound of formula (X) [ka] (In the formula, R 8 , R 8’ , R 8’’ and R 8’’’ are, independently of each other, H or C 1~4 represents an alkyl group, or Or, R 8 and R 8’ and / or R 8’’ and R 8’’’ forms a 5- or 6-membered ring together with N, provided that R 8 , R 8’ , R 8’’ , and R 8’’’ At least one of the groups is not H; X - represents an anion), Water and at least one C 1~8 alkanol or at least one C 2~4 used in a solvent mixture with alkylene diols, And the peak wavelength of the spectrum (λ max ) is particularly preferably photo-oxidation using light in the range of 580 to 780 nm.

[0066] Further details of preferred photo-oxidation methods can be found in WO 2022 / 128852 A1, the entire disclosure of which is incorporated herein by reference.

[0067] In one embodiment, R 8 and R 8’ and / or R 8’’ and R 8’’’ are taken together to form -(CH2)5- or -(CH2)2-NH-(CH2)2- or -(CH2)2-N(C 1~4 alkyl)-(CH2)2- or -(CH2)2-S-(CH2)2- or -(CH2)2-O-(CH2)2-.

[0068] More preferably, R 8 =R 8’’ and / or R 8’ =R 8’’’ More preferably, R 8 =R 8’ =R 8’’ =R 8’’’ is.

[0069] More preferably, the substituent R 8 , R 8’ , R 8’’ , and R 8’’’ is C 1~4 represents an alkyl group, and more preferably R 8 =R 8’ =R 8’’ =R 8’’’ = methyl or ethyl.

[0070] Most preferably, R 8 =R 8’ =R 8’’ =R 8’’’ =CH3.

[0071] In formula (X), - represents an anion. The role of the anion is to balance the charge of the cation, represented by the part in brackets ([)(]) in the above formula. Therefore, in principle, any anion can be used.

[0072] Preferably, X - represents a halide, most preferably chloride.

[0073] Preferably, the compound of formula (X) is methylene blue. More preferably, the compound of formula (X) is in the form of a double salt with zinc chloride, in particular a double salt of methylene blue and zinc chloride, or in the form of a hydrate, preferably methylene blue hydrate (CAS: 122965-43-9).

[0074] The photooxidation mentioned above has a peak wavelength (λ) in its spectrum in the range of 580-780 nm. max It is essential to use light having a

[0075] In one preferred embodiment, the spectrum has a peak wavelength (λ ) in the range of 585 to 625 nm. max ) is used, which corresponds to light perceived as orange.

[0076] In another more preferred embodiment, the peak wavelength (λ max ) in the range of 625 to 740 nm, which corresponds to light perceived as red.

[0077] This light is primarily in the high wavelength range of the visible spectrum.

[0078] In a further preferred embodiment, the light used is characterized in that more than 80% of the light has a wavelength between 525 and 780 nm, preferably more than 80% of the light has a wavelength between 525 and 700 nm, and more preferably more than 65% of the emitted light has a wavelength between 550 and 650 nm.

[0079] In yet another preferred embodiment, the light used is characterized such that more than 80% of the light has a wavelength between 550 and 780 nm, preferably more than 80% of the light has a wavelength between 600 and 760 nm, more preferably more than 65% of the emitted light has a wavelength between 625 and 700 nm, and most preferably more than 85% of the emitted light has a wavelength between 625 and 700 nm.

[0080] It is therefore important that the light used has a spectrum that contains very little light with wavelengths less than 580 nm. It is extremely important that green, blue, and violet light or light with a high concentration of green, blue, and violet in its spectrum has been found to be unsuitable for the above-mentioned photooxidation.

[0081] In one embodiment, the light used for photo-oxidation can be obtained by filtering out undesired wavelengths of light from a light source, for example, a light source having polychromatic or white light emission can be filtered with a filter that blocks undesired wavelengths.

[0082] There are a variety of known and commercially available possibilities for such filters that use different physical processes to filter light, such as absorption, dichroic, monochromatic, bandpass, shortpass, or wedge filters.

[0083] Absorption or cut-off filters are particularly useful.

[0084] It is particularly preferred that the light source is a white LED lamp combined with a filter that blocks wavelengths below 500 nm, most particularly below 625 nm.

[0085] In a further embodiment, the light used for photo-oxidation can be generated by a respective light source emitting light of the desired wavelength. The light source is preferably orange or red light, more preferably an orange or red LED, with a peak wavelength (λ) in its spectrum in the range of 580-780 nm. max ) to provide light.

[0086] A specific example of the light source in this embodiment is a red LED or a red or orange laser, preferably a red or orange LED lamp. Red and orange LED lamps are widely available commercially. Red and orange LEDs can provide high-intensity red or orange light. In a preferred embodiment, a flexible strip having multiple individual LEDs is incorporated into the strip. This allows for ensuring radial orientation of the LEDs around a curved surface, such as a transparent tube, by simply wrapping the strip around the tube, preferably in a spiral fashion.

[0087] A red LED lamp is most preferable as a light source.

[0088] Photooxidation is carried out by reacting water with at least one C 1~8 alkanol or at least one C 2~4 It is carried out in a solvent mixture with an alkylene diol.

[0089] C 1~8 The alkanol is preferably selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, heptanol and hexanol, more preferably selected from the group consisting of methanol, ethanol and isopropanol.

[0090] C 2~4 The alkylene diol is preferably selected from the group consisting of ethane-1,2-diol, propane-1,2-diol, propane-1,3-diol, butane-1,3-diol, butane-1,4-diol, butane-1,2-diol and butane-2,3-diol, and more preferably selected from the group consisting of ethane-1,2-diol, propane-1,2-diol and propane-1,3-diol.

[0091] The solvent mixture is composed of water and at least one C 1~8 alkanol or at least one C 2~4 It is preferably a mixture with an alkylene diol to form a homogeneous phase.

[0092] The solvent mixture is composed of water and at least one C 1~8 alkanol or at least one C 2~4 A more preferred solvent mixture is a mixture of water and C alkylene diol. 1~8 It is a mixture with alkanols.

[0093] A more preferred solvent mixture is water and C 1~6 It is a mixture with alkanols.

[0094] More preferably, the solvent mixture is a mixture of water and methanol and / or ethanol and / or isopropanol. Most preferably, the solvent mixture is a mixture of water and methanol and / or ethanol.

[0095] Preferably, water C 1~8 Alkanols and C 2~4 The volume ratio of the alkylene diol to the total is in the range of 1:10 to 1:1, particularly in the range of 1:5 to 1:2.

[0096] In a highly preferred embodiment, the solvent mixture is a mixture of water and methanol, preferably in a volumetric ratio of water to methanol ranging from 1:20 to 1:2, preferably 1:10 to 1:2, more preferably 1:6 to 1:3, and most preferably 1:4.

[0097] Photo-oxidation is carried out by reacting water with at least one C 1~8 alkanol or at least one C 2~4 An important advantage is that the process is carried out in a solvent mixture consisting of an alkylene diol and an alkylene diol, which is an ecologically and ecotoxicologically very favorable solvent, and is also economically advantageous. It is therefore highly preferred to carry out the process in the absence of chlorinated solvents.

[0098] The concentration of the mixture of compounds of formulae (IIa) and (IIb) is preferably in the range of 0.002 to 2.0 mol / l, more preferably 0.01 to 0.2 mol / l at the start of photooxidation.

[0099] The ratio of the compound of formula (X) to the compounds of formula (IIa) and (IIb) is more preferably in the range of 0.005 to 20 mol %, more preferably 0.05 to 20 mol %, and even more preferably 0.2 to 10 mol %.

[0100] By photoreaction, a mixture of compounds of formulae (IIIa) and (IIIb) is produced by photochemical reaction from a mixture of compounds of formulae (IIa) and (IIb) and oxygen, in particular in a gas mixture containing at least 15% by volume of oxygen.

[0101] In one embodiment, oxygen is used in the form of a mixture comprising oxygen and an inert gas. The amount of oxygen in such a mixture comprising oxygen and an inert gas is preferably at least 15% by volume, in particular at least 20% by volume. Such a mixture may be, for example, a binary mixture, such as an oxygen / nitrogen mixture or an oxygen / argon mixture. The aforementioned mixture may consist of or contain two or more inert gases. It is particularly preferred to use air as such a mixture comprising oxygen and an inert gas.

[0102] In a preferred embodiment, oxygen is used in substantially pure form, ie the amount of oxygen in the gas is between 90% and 100%, more preferably between 95% and 100%, even more preferably between 99% and 100%.

[0103] The photo-oxidation can be carried out at atmospheric pressure or under increased pressure, preferably under increased pressure, in particular under a pressure of more than 2 bar, preferably more than 3 bar, more preferably from 2 to 20 bar.

[0104] The photooxidation is carried out in a suitable photoreactor. Preferred photoreactors are flow reactors, especially spiral flow reactors.

[0105] The individual components can be introduced into the photoreactor separately or as a mixture. Preferably, the reaction mixture is prepared prior to entering the photoreactor.

[0106] The reaction is preferably conducted in a manner in which the oxygen pressure is controlled by appropriate valves and mass flow controllers. Such process control devices and methods for conducting photoreactions using liquids and gases are known to those skilled in the art.

[0107] Preferably, the process is a continuous process, and therefore the photooxidation is preferably carried out in a reactor that allows for a continuous process.

[0108] It has been observed that this photo-oxidation process (step b)) allows obtaining a mixture of the compound of formula (IIIa) (4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one) and the compound of formula (IIIb) in very high yields, preferably greater than 95%, even more preferably greater than 98%, and with very high selectivity.

[0109] [Reduction (step c))] In step c), the mixture of the compound of formula (IIIa) and the compound of formula (IIIb) is reduced with a reducing agent to obtain a mixture of the compound of formula (IV) and the compound of formula (I).

[0110] For the reduction in step c) several reducing agents can be used.

[0111] Suitable reducing agents may be thiosulfates, tertiary phosphines, hydrogen, dithionates, dithionites, sulfites, trialkyl phosphites, iodides, metals, or dialkyl sulfides.

[0112] The reducing agent is preferably selected from the group consisting of Na2S2O3 (sodium thiosulfate), PPh3 (triphenylphosphine), H2 / PdC, Na2S2O4 (sodium dithionite), Na2SO3 (sodium sulfite), P(OEt)3 (triethyl phosphite), NaI (sodium iodide), Zn (and / or other metals), and DMS (dimethyl sulfide).

[0113] The reducing agent is preferably a thiosulfate, particularly sodium thiosulfate.

[0114] The reducing agent is preferably used in large molecular excess, most preferably in an amount of 2 to 10 equivalents relative to the compound of formula (I). The reduction is more preferably carried out in aqueous alcohol, especially at room temperature.

[0115] The reduction can be carried out on a quantitative scale and in very high yields.

[0116] The reduction in step c) can be carried out in a batch or continuous process.

[0117] Step c) is preferably carried out continuously.

[0118] [Rearrangement (step d)] In step d), the mixture of the compound of formula (IV) and the compound of formula (I) is treated with a basic substance at a temperature above 200°C, preferably above 240°C, to rearrange the compound of formula (IV) in the mixture to give the compound of formula (I).

[0119] Examples of such basic substances include alkali metals such as sodium, potassium, lithium, rubidium, and cesium; alkaline earth metals such as calcium, magnesium, barium, and strontium; and basic compounds containing at least one of these metals in their molecular structure. Examples of such basic substances include the following compounds: A. Alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, and barium hydroxide; and B. Alkali metal or alkaline earth metal carbonates and bicarbonates, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, barium carbonate, and magnesium carbonate; and C. alkaline earth metal oxides, such as calcium oxide, magnesium oxide, and barium oxide; and D. Alkali metal or alkaline earth metal containing compounds that have been used as buffering agents in the past, for example, suitable mixtures of alkali dihydrogen phosphates such as monopotassium dihydrogen phosphate and dialkali monohydrogen phosphate such as dipotassium monohydrogen phosphate, or alkali metal salts of organic carboxylic acids such as boric acid, citric acid, lactic acid, tartaric acid, and acetic acid. E. Metal oxides, especially iron oxide.

[0120] Preferably, step d) is carried out in the presence of water. It is further preferred that in step c) at least one water-soluble alcohol is present apart from water, preferably methanol and / or ethanol and / or isopropanol.

[0121] Step d) is preferably carried out in the presence of a basic substance so that the pH is 6.5 or higher, preferably 7 or higher. The most preferred pH of the reaction mixture is 7-14.

[0122] Step d) is preferably carried out under reducing conditions or in an inert atmosphere, in particular nitrogen or argon.

[0123] Preferably, the basic reaction mixture is neutralized with acid at the end of the reaction.

[0124] Preferably, rearrangement step d) is carried out as disclosed in U.S. Pat. No. 3,957,887, in particular Example 12 thereof, or in French Patent No. 2200225 or German Patent No. 2345062, the disclosures of which are incorporated herein in their entirety by reference.

[0125] The reaction of step d) can be carried out in a batch process or a continuous process.

[0126] Preferably, step d) is carried out continuously.

[0127] [Reduction / rearrangement (steps c / d)] In a preferred embodiment, the reduction step c) and the rearrangement step d) are combined into a single step c / d). c / d) reduction / rearrangement of the mixture of compounds of formula (IIIa) and formula (IIIb) by treatment with a basic substance and in the presence of a reducing agent at a temperature above 200°C, preferably above 240°C, to obtain compounds of formula (I). It is implemented as.

[0128] Details of the reduction and rearrangement have already been described for step c) or step d), respectively.

[0129] The present invention demonstrates that 2,3,5-trimethylhydroquinone can be obtained in high yield and selectivity from a mixture of 2,4,6-TMP and 2,3,6-TMP, which can be obtained from either 2,5-dimethylfuran obtained from renewable resources, or a mixture of m-cresol and p-cresol, which are readily and inexpensively available as a mixture in large industrial quantities from commercial suppliers. It is particularly surprising that both components of each mixture can undergo reaction without mutual interference under the same conditions in each of the respective reaction steps.

[0130] As already mentioned, 2,3,5-trimethylhydroquinone is a key component in the synthesis of α-tocopherol.

[0131] Therefore, the present invention also provides a method for producing a pharmaceutical composition comprising: i) providing 2,3,5-trimethylhydroquinone prepared from a mixture of mesitol (formula (IIa)) and 2,3,6-TMP (formula (IIb)) by the process as described in detail above; ii) condensing 2,3,5-trimethylhydroquinone from step i) with a compound of formula (VII-A) or formula (VII-B) to obtain α-tocopherol of formula (VIII); [ka] wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, in particular acetoxy or benzoyloxy, methanesulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); The wavy line represents a carbon-carbon bond that, when connected to a carbon-carbon double bond, is in either the Z or E configuration. The present invention relates to a process for producing α-tocopherol, comprising:

[0132] When Q represents a halide, preferably Q represents Cl.

[0133] When Q represents acyloxy, the acyloxy is preferably of the formula [ka] (In the formula, R 10 is C 1~6 - represents either an alkyl or aryl group, which may optionally in particular be 1~6 -substituted with an alkyl group).

[0134] Preferably, R 10 is C 1~6 represents either an alkyl or phenyl group.

[0135] More preferably, R10 represents either a methyl group or a phenyl group, and most preferably represents a methyl group.

[0136] Specific examples of compounds of formula (VII-a) are isophytol, isophytyl chloride, isophytyl bromide, isophytyl iodide, isophytyl acetate, isophytyl methanesulfonate, isophytyl ethanesulfonate, isophytyl benzenesulfonate and isophytyl toluenesulfonate.

[0137] Specific examples of compounds of formula (VII-B) are phytol, phytyl chloride, phytyl bromide, phytyl iodide, phytyl acetate, phytyl methanesulfonate, phytyl ethanesulfonate, phytyl benzenesulfonate and phytyl toluenesulfonate.

[0138] The compounds of formula (VII-B) can be used as E / Z mixtures as well as in the pure E or pure Z form. Their use as E / Z mixtures is preferred.

[0139] Q preferably represents OH or Cl.

[0140] Therefore, the compound of formula (VII-A) or (VII-B) is preferably phytol, isophytol, phytyl chloride, or isophytyl chloride, more preferably phytol or isophytol, and most preferably isophytol.

[0141] The use of compounds of formula (VII-A) is preferred over compounds of formula (VII-B).

[0142] Condensation step ii) is shown schematically in FIG.

[0143] The condensation reaction of step ii) can be carried out, for example, as described in W. Bonrath et al. Angew. Chem. Int. Ed. 2012, 51, 12982-12985 or Bonrath, W. et al. (2021). Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). In Ullmann's Encyclopedia of Industrial Chemistry. https: / / doi.org / 10.1002 / 14356007.o27_o07.pub2.

[0144] This condensation reaction (step ii)) is preferably carried out using a Lewis acid or a Bronsted acid.

[0145] Said Lewis or Bronsted acids are in particular those described in EP 0949255 A1 and Bonrath et al., Adv. Synth. Catal. 2002, 344:37-39.

[0146] FIG. 1 shows, as detailed above, different preferred synthetic routes for the process of producing 2,3,5-trimethylhydroquinone of formula (I) from a mixture of mesitol (formula IIa) and 2,3,6-TMP (formula IIb).

[0147] FIG. 2 shows schematically different preferred synthetic routes to obtain a mixture of mesitol (Formula IIa) and 2,3,6-TMP (Formula IIb), as detailed above.

[0148] FIG. 3 shows a schematic diagram of the preparation of alpha-tocopherol (formula (VIII)) from 2,3,5-trimethylhydroquinone of formula (I).

[0149] [Example] The present invention is further illustrated by the following experiments.

[0150] [First Experimental Series (Examples 1 to 26): Reaction of 2,5-dimethylfuran with acetylene: Step a0] As shown in Table 1, 2,5-dimethylfuran was reacted with acetylene (2 wt %) in an organic solvent and a platinum catalyst.

[0151] For this purpose, under an argon atmosphere, platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent), and acetylene (1.0 equivalent), dissolved in their respective organic solvents (2% by weight), were added to a 10 ml vial equipped with a magnetic stirrer bar. The vial was then sealed with a cap, and the mixture was stirred in an aluminum block at 23 °C for the time indicated in Table 1. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including unreacted 2,5-dimethylfuran) were removed in vacuo at 50 °C / <30 mbar, yielding an oily residue. The amounts of 2,4- and 2,5-dimethylphenol were determined by GC (gas chromatography). The ratios and yields are shown in Table 1.

[0152] The results in Table 1 show that ligands with aromatic substituents are particularly suitable as part of the platinum catalyst. 5F )3 (tris(pentafluorophenyl)phosphine) is one of the most suitable ligands. Furthermore, Table 1 shows that acetone and 3-pentanone are particularly suitable organic solvents.

[0153] All examples in Table 1 result in mixtures of 2,4-DMP and 2,5-DMP.

[0154] [Table 1]

[0155] [Second Experimental Series (Examples 27 to 37): Reaction of 2,5-dimethylfuran with propyne: Step a0] As shown in Table 2, 2,5-dimethylfuran was reacted with propyne (2 wt %) in an organic solvent and a platinum catalyst.

[0156] For this purpose, under an argon atmosphere, platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent), and propyne (1.0 equivalent), dissolved in their respective organic solvents (2 wt%), were added to a 10 ml vial equipped with a magnetic stirrer bar. The vial was then sealed with a cap, and the mixture was stirred in an aluminum block at 23 °C for the time indicated in Table 2. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including unreacted 2,5-dimethylfuran) were removed in vacuo at 50 °C / <30 mbar, yielding an oily residue. The amounts of 2,4,6-TMP and 2,3,6-TMP were determined by GC (gas chromatography). The ratios and yields are shown in Table 2.

[0157] [Table 2]

[0158] [Third Experimental Series (Examples 37 to 43): Reaction of 2,5-dimethylfuran with MAF] As shown in Table 2, 2,5-dimethylfuran was reacted with MAF gas (2 wt %) in an organic solvent and a platinum catalyst.

[0159] For this purpose, under an argon atmosphere, platinum chloride (6 mol%), 2,5-dimethylfuran (1.0 equivalent), and MAF gas (1.0 equivalent), dissolved in their respective organic solvents (2 wt%), were added to a 10 ml vial equipped with a magnetic stirrer bar. The vial was then sealed with a cap, and the mixture was stirred in an aluminum block at 23 °C for the time indicated in Table 3. The reaction mixture was then filtered to remove the catalyst and ligand. All volatiles (including unreacted 2,5-dimethylfuran) were removed in vacuo at 50 °C / <30 mbar, yielding an oily residue. The amounts of 2,4,6-TMP and 2,3,6-TMP were determined by GC (gas chromatography). The ratios and yields are shown in Table 2.

[0160] [Table 3]

[0161] [Example 44: Methylation: Step a'] A gas-phase flow reactor was charged with an iron oxide-based catalyst (13 g). The reactor was closed and heated under nitrogen until the reactor temperature reached 350°C. The feed consisted of a mixture of 2,5-dimethylphenol and 2,4-dimethylphenol (Example 2) with methanol and water in a molar ratio of 0.35:0.65:30:1.7. The mixture was pumped from top to bottom into the gas-phase reactor at 0.39 ml / min. After the heating zone, the reaction mixture was cooled to room temperature and collected in a bottle. The bottle was emptied and analyzed after 24 hours for 5 days.

[0162] The average conversion and selectivity over the 5 days were: Conversion of 2,5-dimethylphenol: 16% Conversion rate of 2,4-dimethylphenol: 32% Selectivity for 2,3,6-trimethylphenol: 95% Selectivity for 2,4,6-trimethylphenol: 89% It was.

[0163] Example 45: Photooxidation of a mixture of 2,4,6-TMP and 2,3,6-TMP: step b) A solution of a mixture of 2,4,6-TMP (3.3 mmol) and 2,3,6-TMP (1.7 mmol) and methylene blue hydrate ([CAS: 122965-43-9]), 14.4 mg, 0.900 mol %, in methanol and water (4:1, v / v, 250 mL) was prepared to give a homogeneous blue solution.

[0164] The solution was pumped through a high-pressure liquid chromatography pump into a photoreactor (tubing system: inner diameter 0.75 mm, outer diameter 1.58 mm, PFA coil) (liquid flow rate: 0.250–0.023 mL / min, HPLC-tuned piston pump) at a constant pressure of 10 bar.

[0165] Before entering the photoreactor, the solution was air-enriched (air flow rate: 1.350-0.125 mL / min, mass flow controller). In the photoreactor, the reaction mixture was exposed to a Hyper Red LED light source during a residence time of 40 min. Complete conversion was confirmed by thin-layer chromatography and QNMR. The photoreactor was kept at ambient temperature (20 °C). After two residence times, the reaction mixture (25 mL) was collected by round-bottom chromatography. Water (50 mL) was added, and the solution was extracted with pentane (2 × 50 mL) and diethyl ether (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the organic solvent was removed under reduced pressure (15 mbar) to give (4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one) (Formula (IIIa)) (conversion: >99%, yield: 99%) and 2,3,5-trimethylbenzoquinone (=2,3,5-trimethylcyclohexa-2,5-diene-1,4-dione, TMQ) (Formula (IIIb)) (conversion: >99%, yield: 71%).

[0166] [Example 46: Reduction of a mixture of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one and 2,3,5-trimethylbenzoquinone: step c)] Platinum on charcoal (1.0 mol%) was placed in a flame-dried flask and methanol was carefully added to give a dark, heterogeneous solution. A solution of a mixture of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (Formula (IIIa)) and 2,3,5-trimethylbenzoquinone (=2,3,5-trimethylcyclohexa-2,5-diene-1,4-dione, TMQ) (Formula (IIIb)) (0.25 mmol) in methanol and water (4:1, v / v) was prepared to give a yellow, homogeneous solution, which was added to the catalyst solution. The flask was evacuated and then hydrogen was introduced. The reaction mixture was stirred at ambient temperature (20 °C) for > 1 h until conversion was complete. Water (10 mL) was added, and the solution was extracted with diethyl ether (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and the organic solvent was removed under reduced pressure (15 mbar) to give a mixture of 2,3,5-trimethylhydroquinone (Formula (I)) (conversion: >99%, yield: 74%) and 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (Formula (IV)) (conversion: >99%, yield: 51%).

[0167] [Example 47: Rearrangement of 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one to 2,3,5-trimethylhydroquinone: step d] A mixture of 2,3,5-trimethylhydroquinone (Formula (I)) and 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (Formula (IV)) in aqueous NaOH, methanol, and sodium sulfite (6.3 mol % relative to Formula (IV)) was pumped at 10 ml / min through a flow reactor (diameter 1.5 mm, length: 2000 mm) at 250 °C. At the end of the flow reactor, the solution was neutralized with sulfuric acid. The reaction mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo. 2,3,5-trimethylbenzoquinone (Formula (I)) was obtained in a total yield of 92%.

Claims

1. Formula (I) 【Chemistry 1】 A method for producing 2,3,5-trimethylhydroquinone of the formula (I), comprising the following consecutive steps: a) providing a mixture of a compound of formula (IIa) and a compound of formula (IIb); 【Chemistry 2】 b) oxidizing the mixture of compounds of formula (IIa) and formula (IIb) to form a mixture of compounds of formula (IIIa) and formula (IIIb); 【Transformation 3】 c) reducing the mixture of the compound of formula (IIIa) and the compound of formula (IIIb) with a reducing agent to obtain a mixture of the compound of formula (IV) and the compound of formula (I); 【Chemistry 4】 d) treating a mixture of the compound of formula (IV) and the compound of formula (I) with a basic substance at a temperature above 200°C, preferably above 240°C, to rearrange the compound of formula (IV) in the mixture to give the compound of formula (I). 【Transformation 5】 and obtaining said compound.

2. The mixture of compound (IIa) and compound of formula (IIb) is subjected to reaction step a0) a0) reacting a compound of formula (V) with a compound of formula (VI) in the presence of a Pt or Au catalyst, either in the form of a salt or a complex 【Transformation 6】 (Wherein R is H or CH ３ , preferably CH ３ represents); Formula (IIa-1) and Formula (II-b) 【Transformation 7】 with the proviso that when R represents H, the mixture of compounds of formula (IIa-1H) and formula (IIb-1H) is obtained by reaction step a′) 【Transformation 8】 a') Methylating a mixture of formula (IIa-1H) and formula (IIb-1H) to obtain formula (IIa) and formula (IIb) 【Chemistry 9】 2. The method of claim 1, wherein the mixture is subjected to a step of obtaining a mixture of compounds of formula (I).

3. 3. The method according to claim 2, characterized in that the mixture of step a0) is carried out in the presence of a Pt catalyst, either in the form of a Pt salt or a Pt complex.

4. R is CH ３ 4. The process according to claim 2 or 3, characterized in that when the formula (I) represents:

5. The Pt catalyst is a Pt(II) salt, particularly PtCl ２ The method according to any one of claims 2 to 4, characterized in that

6. 6. The method according to claim 2, wherein the Pt catalyst is a complex of Pt(II) with at least one organic ligand containing at least one phosphorus atom, in particular a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines.

7. The Pt catalyst is prepared by the reaction of PtCl 2 in the presence of an organic ligand containing at least one phosphorus atom, in particular a ligand selected from the group consisting of phosphites, phosphates, phosphonates, and phosphines. ２ The method according to any one of claims 2 to 6, characterized in that:

8. The organic ligand is preferably triphenylphosphite (P(OPh) ３ ), diphenyl phosphate ((PhO) ２ P=O(OH)), triphenyl phosphate ((PhO) ３ P=O), triethyl phosphate ((EtO) ３ P=O), dibenzyl phosphite ((PhCH ２ O) ２ P=O(H)), methyl diphenyl phosphite ((MeO)P(OPh) ２ ), triphenylphosphine (P(Ph) ３ ), P(Ph ５Ｆ ) ３ , bis-(2,2,2-trifluoroethyl)-phosphite ((CF ３ CH ２ O) ２ P=O(H)), triethyl 2-fluoro-2-phosphonoacetate ((CHFCOOEt)(EtO) ２ P=O), tris(2-tolyl)phosphite, ethyl 3-(diethoxyphosphoryl)propanoate (=triethyl 3-phosphonopropionate) ((CH ２ CH ２ COOEt) (EtO) ２ P=O), 2-(diphenylphosphino)benzoic acid (P(Ph) ２ C ６ H ４ COOH), 3,9-bis(2,4-di-tert-butylphenoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, P(O-isooctyl) ３ ), P(O-isopropyl) ３ ), P(Oi-PrF ６ ) ３ , P(On-Bu) ３ , bis(2,4-di-tert-butylphenoxy)-λ2-phosphane, CH ３ P(EtO) ２ , 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (= 4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine 4-oxide), VAPOL hydrogen phosphate (= 18-hydroxy-8,9-diphenyldiphenanthro[4,3-d:3',4'-f][1,3,2]dioxaphosphepine 18-oxide), methyltriphenoxyphosphonium iodide ([CH ３ P(OPh) ３ ] ＋ I － , 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane ((CH ２ CH ２ COOEt) (EtO) ２ P=O, trimethylolpropane phosphite), trisodium triphenylphosphine trisulfonate (=TPPTS), disodium triphenylphosphine disulfonate (=TPPDS) and sodium triphenylphosphine monosulfonate (=TPPMS); In the formula, Ph represents phenyl; ５Ｆ 8. The method according to claim 6 or 7, characterized in that: denotes pentafluorophenyl; Et denotes ethyl; and Me denotes methyl.

9. The mixture of compound (IIa) and compound of formula (IIb) is subjected to reaction step a″) a″) Methylation of a mixture of p-cresol of formula (0p) and m-cresol of formula (0m) 【Chemistry 10】 2. The process according to claim 1, characterized in that a mixture of compounds of formula (IIa) and formula (IIb) is obtained by

10. The oxidation step b) comprises oxidizing oxygen and a compound of formula (X) 【Chemistry 11】 (In the formula, R ８ , R ８’ , R ８’’ , and R ８’’’ are each independently H or C １～４ represents either an alkyl group; Or, R ８ and R ８’ and / or R ８’’ and R ８’’’ forms a 5- or 6-membered ring together with N, However, R ８ , R ８’ , R ８’’ , and R ８’’’ at least one of the groups is not H; X － represents an anion), Water and at least one C １～８ alkanol or at least one C ２～４ used in a solvent mixture with alkylene diols, And the peak wavelength of the spectrum (λ ｍａｘ 10. The method according to claim 1, wherein the oxidation step is photo-oxidation using light in the range of 580 to 780 nm.

11. The light used has a peak wavelength (λ ｍａｘ 11. The method of claim 10, wherein the wavelength of the incident light is in the range of 625 to 740 nm.

12. 12. Method according to claim 10 or 11, characterized in that the light source is a white LED lamp combined with a filter cutting off wavelengths below 500 nm, in particular below 625 nm.

13. 12. The method according to claim 10 or 11, characterized in that the light source is a red LED lamp.

14. 14. The process according to any one of claims 10 to 13, characterized in that the solvent mixture is a mixture of water with methanol and / or ethanol and / or isopropanol.

15. R ８ =R ８’ =R ８’’ =R ８’’’ =CH ３ 15. The process according to any one of claims 10 to 14, characterized in that X represents a halide, in particular a chloride.

16. 16. The method according to any one of claims 1 to 15, characterized in that the reduction step c) is carried out in the presence of a reducing agent selected from the group consisting of thiosulfates, tertiary phosphines, hydrogen, dithionates, dithionites, sulfites, trialkylphosphites, iodides, metals, or dialkylsulfides.

17. A method for producing α-tocopherol, comprising: i) providing 2,3,5-trimethylhydroquinone prepared from a mixture of mesitol (formula (IIa)) and 2,3,6-TMP (formula (IIb)) by the method according to any one of claims 1 to 16; 【Chemistry 12】 ii) condensing 2,3,5-trimethylhydroquinone from step i) with a compound of formula (VII-A) or (VII-B) to obtain α-tocopherol of formula (VIII); 【Chemistry 13】 in which Q is a substituent selected from the group consisting of OH, halide, acyloxy, in particular acetoxy or benzoyloxy, methanesulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); and The wavy line, when connected to a carbon-carbon double bond, represents a carbon-carbon bond that is in either the Z or E configuration.

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