Photooxidation of 2,4,6-trimethylphenol

Abstract

The present invention relates to the photooxidation of 2,4,6-trimethylphenol using light in the long wavelength region of the visible spectrum with methylene blue as a photosensitizer in a solvent mixture of water and alcohol to give 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, which can be used to obtain 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one and 2,3,5-trimethylhydroquinone in high yield and high selectivity from 2,4,6-trimethylphenol.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the preparation of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one and 2,3,5-trimethylhydroquinone, in particular to the field of photooxidation of 2,4,6-trimethylphenol (=mesitol).

[0002] [Background technology] 2,3,5-Trimethylhydroquinone is a key intermediate in the production of α-tocopherol.

[0003] T. Netscher, in Vitam. Horm. 2007, 76, 155-202, especially p. 159, and W. Bonrath et al., in Angew. Chem. Int. Ed. 2012, 51, 12960-12990, especially p. 12983, disclose that 2,3,5-trimethylhydroquinone can be obtained by catalytic methylation of m-cresol to 2,3,6-trimethylphenol, which is then oxidized to 2,3,5-trimethylbenzoquinone, which is subsequently reduced to 2,3,5-trimethylhydroquinone. An alternative process starts with isophorone using an oxidation / hydrogenation / isomerization sequence. Another process uses mesitol as a starting material and uses oxidation and rearrangement to produce 2,3,5-trimethylhydroquinone.

[0004] U.S. Patent Application Publication No. 2012 / 0203013A1 discloses the oxidation of 2,4,6-trimethylphenol (mesitol) with hydrogen peroxide in the presence of a bismuth catalyst. MC Carreno et al., Angew. Chem. Int. Ed. 2006, 45, 2737-2741, disclose that the oxidation of mesitol can be carried out with oxone in acetonitrile.

[0005] Murtinho D. et al., J. Chem. Soc. Perkin Trans. 2, 2000, 2441-2447, proposed the photooxidation of 2,3,5-trimethylphenol with oxygen in the presence of a photosensitizer to obtain 2,3,5-trimethylbenzoquinone. In particular, methylene blue was disclosed as a photosensitizer for obtaining 1,5-dihydroxynaphthalene in a mixture of acetonitrile and dichloromethane. However, the yield was not very high, only 78-82%, so the use of a porphyrin-type photosensitizer instead was proposed. This type of porphyrin compound is somewhat expensive and not easily available commercially. On the other hand, both acetonitrile and dichloromethane are solvents with significant environmental and ecotoxicological disadvantages. Furthermore, it is known that oxidizing phenol is much more difficult than oxidizing naphthol.

[0006] In contrast to 2,3,5-trimethylphenol, mesitol (=2,4,6-trimethylphenol) is readily available. It would be of great commercial interest to provide a process for producing 2,3,5-trimethylhydroquinone starting from mesitol instead of m-cresol or 2,3,5-trimethylphenol, respectively.

[0007] [Summary of the Invention] Therefore, an object of the present invention is to provide an efficient method for synthesizing 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, or 2,3,5-trimethylhydroquinone in high yield and high selectivity, respectively.

[0008] It has been found that the photo-oxidation according to claim 1 or the method according to claim 12 or 14, respectively, provides an efficient way to solve this problem.

[0009] In the present invention, methylene blue, a highly attractive photosensitizer that is readily available and cost-effective, can be used, resulting in not only very high yields at high conversions but also very high selectivities to the desired products. A particular advantage is that this process can be carried out in the absence of chlorinated solvents. Therefore, the aforementioned process is very attractive for industrial applications.

[0010] Further aspects of the invention are the subject matter of further independent claims. Particularly preferred embodiments are the subject matter of the dependent claims.

[0011] [Detailed Description of the Invention] In a first aspect, the present invention provides a method for producing a medicament for a medicament comprising: Oxygen and formula (III): [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, 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 Group, R 8’ Group, R 8’’ groups, 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, The peak wavelength of the spectrum (λ max ) in the range of 580 to 780 nm, to carry out photo-oxidation, [ka] The present invention relates to a method for producing the same.

[0012] For clarity, some terms used in this document are defined as follows: In this document, "C x~y An "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.

[0013] Similarly, C x~y Alkanol or C x~y Alkylene diols are alcohols containing x to y carbon atoms, each having one or two OH groups and each having an alkyl or alkylene group.

[0014] In this document, where the same subscript for a symbol or group occurs in more than one formula, the definition of said group or symbol given in relation to one particular formula also applies to other formulas containing the same subscript.

[0015] The peak wavelength is the wavelength at which the intensity of the spectrum is greatest.

[0016] In the method, 2,4,6-trimethylphenol (= the compound of formula (II), mesitol) is photooxidized to give 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (= the compound of formula (I)).

[0017] Mesitol is a known chemical, commercially available in large quantities from a variety of sources, and can be readily prepared, for example, by reaction of mesitylene with peroxymonophosphate.

[0018] In the photooxidation, a photosensitizer of formula (III) is used [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, 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 Group, R 8’ Group, R 8’’ groups, and R 8’’’ At least one of the groups is not H; X - represents an anion).

[0019] In one embodiment, R 8 and R 8’ and / or R 8’’ and R 8’’’ together 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-.

[0020] More preferably, R 8 =R 8’’ and / or R 8’ =R 8’’’ More preferably, R 8 =R 8’ =R 8’’ =R 8’’’ is.

[0021] More preferably, the substituent R 8 , R 8’ , R 8’’ , and R 8’’’ is C 1~4 represents an alkyl group, and more preferably R8 =R 8’ =R 8’’ =R 8’’’ = methyl or ethyl.

[0022] Most preferably, R 8 =R 8’ =R 8’’ =R 8’’’ =CH3.

[0023] In formula (III), X - represents an anion. The role of the anion is to balance the charge on the cation, which is represented as the part inside the square brackets ([)(]) in the above formula. Therefore, in principle, any anion can be used.

[0024] Preferably, X - represents a halide, most preferably chloride.

[0025] Preferably, the compound of formula (III) is methylene blue. More preferably, the compound of formula (III) 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).

[0026] Photosensitizers of formula (III) have been found to be particularly suitable for the photooxidation of compounds of formula (II).

[0027] In order to carry out the above-mentioned photo-oxidation, the peak wavelength (λ max It is essential to use light with a wavelength in the range of 580 to 780 nm.

[0028] In a preferred embodiment, the peak wavelength (λ max ) in the range of 585 to 625 nm, which corresponds to light perceived as orange.

[0029] In another more preferred embodiment, the peak wavelength (λmax ) in the range of 625 to 740 nm, which corresponds to light perceived as red.

[0030] This light is primarily in the high wavelength range of the visible spectrum.

[0031] 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.

[0032] 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.

[0033] 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 content of green, blue, and violet in its spectrum has been found to be unsuitable for the above-mentioned photooxidation.

[0034] 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 polychromatic or white emitting light source can be screened with filters that block undesired light.

[0035] 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.

[0036] Absorption or cut-off filters are particularly useful.

[0037] 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.

[0038] A red LED lamp is most preferable as a light source.

[0039] Figure 1a shows a schematic diagram of this embodiment. A light source (1) emits radiation of various wavelengths, including desired wavelengths (2a) and undesired wavelengths (2b). The light source is preferably white light, more preferably a white LED. A filter (6) is placed between the light source (1) and a photoreactor having transparent walls (4). The filter (6) filters out the undesired wavelengths of light, thereby reducing the peak wavelength (λ) of the spectrum. max The filter (6) is preferably an "orange filter" or a "red filter", i.e., a filter that transmits only light having a wavelength between 585 and 625 nm or between 625 and 740 nm. The filter (6) is a mixture of at least oxygen and the compound of formula (II), water, and at least one C 1~8 alkanol or at least one C 2~4 The reaction mixture (3), which comprises a solvent mixture of alkylene diol, is inside the photoreactor (5).

[0040] By photoreaction, the compound of formula (I) is produced by photochemical reaction from the compound of formula (II) and oxygen, in particular in a gas mixture containing at least 20% by volume of oxygen.

[0041] A particularly preferred example of this embodiment is a white LED, whose light is filtered so that all light other than the desired wavelengths is blocked, or at least largely absorbed (e.g., using an "orange filter" (which transmits only light between 585 and 625 nm) or a "red filter" (which transmits only light between 625 and 740 nm)).

[0042] Therefore, the source of light is preferably a white LED lamp in combination with a filter that blocks wavelengths below 500 nm, in particular below 625 nm.

[0043] In a further embodiment, the light used for photo-oxidation can be generated by a respective light source that emits light of the desired wavelength.

[0044] Figure 1b is a schematic diagram of this embodiment. The light source (1) emits light of a desired wavelength (2a) so that the peak wavelength (λ max The light source preferably provides light having a peak wavelength (λ ) in the range of 580 to 780 nm. max ) is an orange or red LED for providing light using a light source in the range of 580 to 780 nm.

[0045] at least oxygen and a compound of formula (II), water and at least one C 1~8 alkanol or at least one C 2~4 The reaction mixture (3) containing the alkylene diol solvent mixture is inside the photoreactor (5). The compound of formula (I) is produced by photochemical reaction of the compound of formula (II) with oxygen.

[0046] 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.

[0047] Photooxidation is carried out by reacting water with at least one C 1~8 alkanol or at least one C 2~4It is carried out in a solvent mixture with an alkylene diol.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] The solvent mixture is composed of water and at least one C 1~8 alkanol or at least one C 2~4 Preferably, the solvent mixture is a mixture of water and C alkylene diol. 1~8 It is a mixture with alkanols.

[0052] A more preferred solvent mixture is water and C 1~6 It is a mixture with alkanols.

[0053] 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.

[0054] Preferably, water C1~8 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.

[0055] In a highly preferred embodiment, the solvent mixture is a mixture of water and methanol, preferably with a volume ratio of water to methanol in the range of 1:20 to 1:2, preferably in the range of 1:10 to 1:2, more preferably in the range of a ratio of 1:6 to 1:3, and most preferably 1:4.

[0056] 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 of the present invention 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. Therefore, it is highly preferred to carry out the process in the absence of chlorinated solvents.

[0057] The concentration of the compound of formula (II) 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.

[0058] It is further preferred that the ratio of the compound of formula (III) to the compound of formula (II) is in the range of 0.005 to 20 mol %, preferably 0.05 to 20 mol %, more preferably 0.2 to 10 mol %.

[0059] 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.

[0060] 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%.

[0061] 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.

[0062] The photooxidation is carried out in a suitable photoreactor. Preferred photoreactors are flow reactors, especially spiral flow reactors.

[0063] 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.

[0064] In one preferred embodiment, the oxygen-containing solvent mixture is mixed with the compound of formula (II) before it enters the photoreactor.

[0065] In another preferred embodiment, the solvent mixture is mixed with the compound of formula (II) that already contains oxygen before entering the photoreactor.

[0066] In a most preferred embodiment, oxygen is added to a premix comprising at least the compound of formula (II) and the solvent mixture.

[0067] 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.

[0068] Preferably, the process is a continuous process, and therefore the photooxidation is preferably carried out in a reactor that allows for a continuous process.

[0069] 4-Hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (I)) can be obtained by this photooxidation process (step a) in very high yields, preferably greater than 95%, more preferably greater than 98%, and with very high selectivity.

[0070] In a further aspect, the present invention provides a process for preparing a compound of formula (IV) from a compound of formula (II), comprising the steps of: a) photo-oxidizing the compound (II) detailed above to give a compound of formula (I) [ka] obtaining a compound of formula (I); b) reducing the compound of formula (I) with a reducing agent to give a compound of formula (IV) [ka] obtaining a compound of formula (I); The present invention relates to a method comprising:

[0071] For the reduction of the compound of formula (I) in step b), several reducing agents can be used.

[0072] Suitable reducing agents may be thiosulfates, trialkylamines, tertiary phosphines, hydrogen, dithionates, sulfites, trialkyl phosphites, iodides, metals, or dialkyl sulfides.

[0073] The reducing agent is preferably selected from the group consisting of Na2S2O3 (sodium thiosulfate), NEt3 (triethylamine), 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).

[0074] The reducing agent is preferably a thiosulfate, particularly sodium thiosulfate.

[0075] 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.

[0076] Reduction is indicated by a color change to pink.

[0077] The reduction of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (I)) can be carried out on a quantitative scale to give yields of 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (IV)) of greater than 90%, preferably greater than 92%.

[0078] The reduction in step b) can be carried out in a batch or continuous process.

[0079] Step b) is preferably carried out continuously.

[0080] For example, the addition of the reducing agent can be carried out at the end of the photoreactor described above. Furthermore, the reduction of step b) is preferably carried out in a flow reactor.

[0081] Figures 4a and 4b show these embodiments in more detail.

[0082] In a further aspect, the present invention provides a process for preparing a compound of formula (IV) from a compound of formula (II), comprising the steps of: a) photo-oxidation of compound (II) as detailed above to give the compound of formula (I) [ka] obtaining a compound of formula (I); b) reducing the compound of formula (I) with a reducing agent to give a compound of formula (IV) [ka] obtaining a compound of formula (I); c) treating a compound of formula (IV) with a basic substance at a temperature >200°C, preferably >240°C, to give a compound of formula (V) [ka] obtaining a compound of formula (I); Includes.

[0083] Steps a) and b) have already been described in detail above. Figure 6 shows a schematic of the reaction sequence of steps a), b) and c).

[0084] In step c), the compound of formula (IV) is treated with a basic agent at a temperature >200°C, preferably >240°C, to give the compound of formula (V).

[0085] The basic substance may be, in particular, an alkali metal such as sodium, potassium, lithium, rubidium, or cesium; an alkaline earth metal such as calcium, magnesium, barium, or strontium; or a basic compound containing at least one of these metals in its 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.

[0086] Preferably, step c) is carried out in the presence of water. It is further preferred that in step c) at least one water-soluble alcohol, preferably methanol and / or ethanol and / or isopropanol, is present apart from water.

[0087] Step c) 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.

[0088] Step c) is preferably carried out under reducing conditions or in an inert atmosphere, in particular nitrogen or argon. Step c) is preferably carried out in the presence of a reducing substance. Examples of such reducing substances are sodium sulfite (NaSO), sodium bisulfite (NaHSO), sodium dithionite (NaSO), and sodium thiosulfate (NaSO).

[0089] Preferably, the basic reaction mixture is neutralized with acid at the end of the reaction.

[0090] Preferably, reaction step c) is carried out as disclosed in US Pat. No. 3,957,887, in particular as described in Example 12 thereof.

[0091] The reaction of step c) can be carried out in a batch process or a continuous process.

[0092] Step c) is preferably carried out continuously.

[0093] Step c) can be carried out simultaneously with step b) or after step b). In other words, the intermediate formed in step b) can be further reacted directly with the compound of formula (V) using appropriate conditions in reduction step b). However, it is preferred that step c) is carried out after step b) has been carried out, preferably completely.

[0094] Step c) is preferably carried out in a flow reactor.

[0095] Preferably, step c) is carried out in a flow reactor located after the flow reactor in which step b) is carried out. In another embodiment, the reaction of step b) is carried out at the downstream end of a continuous reactor in which reaction step b) is carried out.

[0096] In yet another embodiment, reaction steps a), b) and c) are all carried out in one flow reactor, with the photo-oxidation (step a)) taking place first, followed by the downstream reduction of step b), and then the further downstream reaction step.

[0097] Figures 5a, 5b and 5c show these embodiments in more detail.

[0098] The present invention demonstrates that 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, or 2,3,5-trimethylhydroquinone can be obtained in high yield and selectivity, respectively. In particular, it can be shown that all of these substances can be obtained in high yield and selectivity using a mesitol-based process. It can be shown that this process can produce 2,3,5-trimethylhydroquinone from mesitol in an overall yield (steps a), b), and c) of more than 84%. [Brief explanation of the drawings]

[0099] [Figure 1a] FIG. 1 shows a schematic diagram of photooxidation using a light source and filters to generate light whose spectral peak wavelength (λmax) is in the range of 580-780 nm. [Figure 1b] A schematic diagram of photooxidation using a light source whose spectrum peak wavelength (λmax) is in the range of 580 to 780 nm is shown. [Figure 2a] A schematic diagram of one experimental setup is shown. [Figure 2b] Schematic diagrams of different experimental setups are shown. [Figure 2c] Schematic diagrams of other different experimental setups are shown. [Figure 3] 1 shows the normalized emission spectra of the light for photooxidation using various filters as well as the white light and red LED used in the experiment. [Figure 4a] 1 shows a schematic diagram of a continuous reactor for step b). [Figure 4b] FIG. 1 shows a schematic diagram of an embodiment in which step b) is performed at the end of the photoreactor of step a). [Figure 5a] 1 shows a schematic diagram of a continuous reactor for step c). [Figure 5b] FIG. 1 shows a schematic diagram of an embodiment in which steps c) and b) are performed at the end of the photoreactor of step a). [Figure 6] A schematic reaction scheme of steps a), b) and c) is outlined below.

[0100] In Figure 2a, one preferred experimental layout is shown, which comprises a mixture of at least a compound of formula (II) and a photosensitizer of formula (III), water and at least one C 1~8 alkanol or at least one C 2~4A vessel containing a premix (10) comprising a solvent mixture with alkylene diol is pumped into the photoreactor (5) by a pump (7). Before entering the photoreactor (5), oxygen (11), preferably in the form of air, is mixed with the premix to form the photooxidation reaction mixture (3). The amount of oxygen mixed is controlled by a mass flow controller (8). Around the transparent wall (4) of the linear tubular photoreactor (5), light sources (1) are arranged, in particular in a spiral arrangement of LEDs. The light sources (1) are white LEDs in one embodiment. A filter (6) is placed between the transparent wall (4) and the light source (1) to filter out the peak wavelength (λ) of its spectrum. max The filter (6) can supply light (2a) having a peak wavelength (λ) in the spectrum of the light in the range of 580 to 780 nm. max ) is an orange filter or a red filter for providing specific light in the range of 585-625 nm or 625-740 nm, respectively. In another preferred embodiment, the light source (1) is either an orange LED or a red LED, in particular a red LED, in which case the filter (6) is not present. The photoreactor (5) is preferably a spiral flow reactor. At the outlet of the photoreactor, a backpressure regulator (9) is placed before the product is collected in a collection vessel (12).

[0101] This experimental layout, especially the light source and photoreactor combination, is preferably used for larger scale photoreactions.

[0102] In Figure 2b, another preferred experimental layout is shown, in which at least a compound of formula (II) and a photosensitizer of formula (III) and water and at least one C 1~8 alkanol or at least one C 2~4 A premix (10) containing a mixture of alkylene diol and solvent is pumped from a vessel to a photoreactor (5) using a pump (7). Before the premix enters the photoreactor (5), oxygen (11) is added to form a photooxidation reaction mixture (3). The amount of oxygen added is adjusted using a mass flow controller (8).

[0103] In one embodiment, the light source (1) is a white LED. A filter (6) is placed between the transparent wall (4) of the photoreactor (5) and the light source (1) to filter out the peak wavelength (λ) of its spectrum. max ) can provide light (2a) in the range of 580-780 nm. In this representation, only one light source (1) and one filter (6) are shown. Naturally, several such light sources (1) combined with filters (6) can be arranged around the photoreactor (5) in the form of a spiral flow reactor, allowing even illumination of the entire photoreactor (5). The filter (6) specifically selects the peak wavelength (λ) of the spectrum of the light to be emitted. max ) is an orange filter or a red filter to provide specific light in the range of 585-625 nm or 625-740 nm, respectively. Light having undesired wavelengths (2b) is blocked by filter (6). In another preferred embodiment, light source (1) is either an orange LED or a red LED, more preferably a red LED, in which case filter (6) is not present. A backpressure regulator (9) is placed at the outlet of the photoreactor before the product is finally collected in collection vessel (12).

[0104] This experimental layout, especially the light source and photoreactor combination, is preferably used for smaller volume photoreactions.

[0105] In Figure 2c, another preferred experimental layout is shown, which comprises a mixture of at least a compound of formula (II) and a photosensitizer of formula (III), water and at least one C 1~8 alkanol or at least one C 2~4 A vessel containing a premix (10) comprising an alkylene diol and a solvent mixture is pumped by pump (7) into the photoreactor (5). Prior to entering the photoreactor (5), oxygen (11), preferably in the form of air, is mixed with the premix to form the photooxidation reaction mixture (3). The amount of oxygen mixed is controlled by a mass flow controller (8).

[0106] In this embodiment, a light source (1), preferably a red LED, is arranged in the hollow space formed by the helical turns of a spiral flow reactor (5).

[0107] In one embodiment, the light source (1) is a white LED. A filter (6) is placed around the light source (1), i.e., between the transparent wall (4) of the photoreactor (5) and the light source (1), to filter the peak wavelength (λ) of its spectrum. max The filter (6) can supply light (2a) having a peak wavelength (λ) between 580 and 780 nm. max ) is an orange filter or a red filter, preferably a red filter, for supplying specific light in the range of 585 to 625 nm or 625 to 740 nm, respectively. Light (2b) having undesired wavelengths is filtered by filter (6). In another preferred embodiment, the light source (1) is either an orange or red LED, preferably a red LED, in which case the filter (6) is not present. At the outlet of the photoreactor, a backpressure regulator (9) is placed before the product is finally collected in a collection vessel (12).

[0108] This experimental layout, especially the light source and photoreactor combination, is preferably used for smaller volume photoreactions.

[0109] In yet another embodiment, the light source (1) and filter (6) of Figures 2b) and 2c) are combined, in other words the filter and light source can be arranged on the outside of the photoreactor wall arranged inside and outside the space formed by the helical turns of the spiral flow photoreactor (5).

[0110] FIG. 4a shows a preferred experimental layout of reaction step b), which allows the reduction of the compound of formula (I) to be carried out continuously. The compound of formula (I) (13) is pumped by pump (7) into the reduction reactor (14), to which the reducing agent (15) is also added by pump (7). In a variant of this, the addition of the compound of formula (I) and the reducing agent is realized before the compound of formula (I) enters the reactor (14). If an additional component (not shown in FIG. 4a) is used in the reduction, the additional component may be added to either the reducing agent (15) or the compound of formula (I) (13), or may be fed separately to the reduction reactor (14). In the reduction reactor (14), the compound of formula (I) is reduced to the compound of formula (IV) and transferred from the reactor to a collection vessel (12) for the compound of formula (IV).

[0111] Figure 4b shows a more preferred experimental layout of reaction steps a) and b), which allows both the photoreaction of mesitol and the reduction of the compound of formula (I) to be carried out continuously. The embodiment shown essentially corresponds to a combination of the diagrams shown in Figures 2c and 4a. However, in this embodiment, the compound of formula (I) is transported directly from the outlet of the photoreactor (5) to the inlet of the reactor, where it is reduced to the compound of formula (IV).

[0112] A preferred experimental layout for reaction step c) is shown in Figure 5a. Compound (16) of formula (IV) is pumped by pump (7) into heat treatment reactor (17), to which basic substance (18) is also added by pump (7). In a variant of this, the addition of compound (IV) and basic substance is realized before compound (IV) enters reactor (17). If further components (not shown in Figure 5a) are used in the heat treatment, said further components may be added to either basic substance (18) or compound (16) of formula (IV), or may be fed separately to heat treatment reactor (17).

[0113] In the thermal treatment reactor (17), the compound of formula (IV) is converted to a compound of formula (V), which is transferred from the reactor to a collection vessel (12) for the compound of formula (V).

[0114] Figure 5b shows a more preferred experimental layout of reaction steps a), b), and c), which allows the photoreaction of mesitol, the reduction of the compound of formula (I), and the thermal treatment of the compound of formula (IV) to be carried out all consecutively. The embodiment shown essentially corresponds to a combination of the diagrams shown in Figures 4b and 5a. However, in this embodiment, the compound of formula (IV) is transferred directly from the outlet of the reduction reactor (14) to the inlet of the reactor for the thermal treatment of the compound of formula (IV) to the compound of formula (V). [Explanation of symbols]

[0115] 1 light source 2a Light of the desired wavelength 2b Undesirable wavelengths of light 3. Photooxidation reaction mixture 4. Transparent walls of the photoreactor 5. Photoreactor 6 Filters 7. Pump 8 Mass Flow Controller 9 Back pressure regulator 10 Premix 11 Oxygen 12 Collection container 13 Compound of formula (I) 14 Reduction reactor 15 Reducing Agents 16 Compound of formula (IV) 17 Heat treatment reactor 18 Basic substances

[0116] [Example] The present invention is further illustrated by the following experiments.

[0117] Example 1: Photooxidation of 2,4,6-trimethylphenol (step a) In the following experiments, the experimental layout shown schematically in Figure 2c was used:

[0118] The solvent premix (10), the solvent mixture and the vessels containing the substance to be photooxidized and the photosensitizer, respectively, are pumped by a pump (7) into the photoreactor (5), which is a spiral flow reactor. Before entering the photoreactor (5), oxygen in the form of air (11) is mixed with the premix, which forms the photooxidation reaction mixture (3). The amount of air mixed is controlled by a mass flow controller (8). The light source (1) emits light from red LEDs (12 x OSLON® SSL Hyper red, λ max = 660 nm, 12 LEDs for approximately 9 W & 700 lm, GH CSSPM1.24, viewing angle 120°, CPU cooling system (10 V) to maintain ambient temperature (approximately 20°C) (no filters used) (see spectrum shown as LSr in Figure 3) so that light of the desired wavelength (2a) hits the transparent wall (4) of the photoreactor (5). The photoreactor (5) is wrapped on an inner glass cylinder around a fan-cooled LED lamp (1). At the exit of the photoreactor, a backpressure regulator (9) is placed before the product is finally collected in a collection vessel (12).

[0119] More precisely, the photooxidation was carried out as follows: 2,4,6-trimethylphenol (20.0 mmol L -1 A solution of 2.00 mmol [during the reaction period], 1.0 equivalent) and methylene blue hydrate (0.180 nmol, 0.900 mol % [CAS: 122965-43]-9]) in methanol and water (4:1, v / v) gives a homogeneous blue solution. This solution is pumped through a high-pressure liquid chromatography pump (Dionex P580) into the photoreactor (tubing system: inner diameter 0.75 mm, outer diameter 1.58 mm, PFA coil) at a constant pressure of 10 bar (liquid flow rate: 0.093 mL / min, HPLC-regulated piston pump) (regulated by a backpressure regulator, Equilibar Zero-Flow ZF1 backpressure regulator, computer-controlled).

[0120] Before entering the photoreactor, the solution is enriched with air (air flow rate: 0.500 mL / min, mass flow controller, Bronkhorst El-FLOW, model: FG-200CV-AAD-22-K-DA-000S / N: M19209993A). Within the photoreactor, the reaction mixture is illuminated with a red LED light source (12x OSLON® SSL Hyper red, λ max = 660 nm, 12 LEDs at approximately 15 W & 700 lm, GH CSSPM1.24, viewing angle 120° (see spectrum shown as LSr in Figure 3) during a 40 min residence time. Complete conversion was confirmed by thin layer chromatography (4:1 cyclohexane / EtOAc, R f (substrate)=0.63, R f The reaction mixture (100 mL) was collected in a 250 mL round-bottom flask equipped with a septum and a needle outlet to prevent overpressure. Methanol was removed under reduced pressure (15 mbar) until a constant residual volume was reached. Water (50 mL) was added to the residue, and the solution was extracted with ethyl acetate (3 × 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-one (340 mg, 99% yield) as a green-gray viscous wax.

[0121] Example 2: Reduction of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (step b) In a 50 mL round-bottom flask, place the yellow solution of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (300 mg, 1.78 mmol, 1.0 equiv.) prepared in Example 1 and sodium thiosulfate (1.40 g, 8.90 mmol, 5.0 equiv.) in methanol and water (25 mL, 4:1 v / v). Analyze by thin-layer chromatography (4:1 cyclohexane / EtOAc, R f (substrate)=0.3, Rf The reaction mixture is stirred at ambient temperature until complete conversion is observed with (product) = 0.2). A color change of the solution from yellow to pink is observed. Methanol is removed under reduced pressure. Water (30 mL) is added to the residue, and the solution is extracted with ethyl acetate (3 × 25 mL). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and the organic solvent is removed under reduced pressure (15 mbar) to give 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one as a yellow-green viscous wax (253 mg, 93% yield).

[0122] Example 3: Formation of 2,3,5-trimethylhydroquinone (step c) In the following experiments, the experimental layout shown schematically in Figure 5a was used:

[0123] A solution of 4-hydroxy-2,4,6-trimethyl-2,5-cyclohexadien-1-one (4.7 g, 30 mmol) obtained in Example 2 in aqueous NaOH (440 mL, 0.008 mol / L), methanol (50 mL), and sodium sulfite (235 mg, 1.9 mmol) was pumped through a flow reactor (diameter 1.5 mm, length: 2000 mm) at 250 °C at 10 mL / min. The solution was neutralized with sulfuric acid (1.47 mL) at the end of the flow reactor. The reaction mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo. 2,3,5-trimethylbenzoquinone (4.45 g, 95%) was obtained in 92% yield.

Claims

1. A method for producing a compound of formula (I) from a compound of formula (II): Oxygen and the following formula (III): 【Chemistry 1】 (In the formula, R ８ , R ８’ , R ８’’ and R ８’’’ are, independently of one another, H or C １～４ represents 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 group, R ８’ group, R ８’’ group, 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, The peak wavelength of the spectrum (λ ｍａｘ ) in the range of 580 to 780 nm, to convert the compound of the following formula (II) to the compound of the following formula (I): 【Chemistry 2】 A method for manufacturing the above.

2. 2. The method according to claim 1, wherein the light used has a spectral peak wavelength (λmax) in the range of 625 to 740 nm.

3. 3. The method of claim 1, wherein more than 80% of the light has a wavelength between 525 and 780 nm.

4. 4. The process according to claim 1, wherein the solvent mixture is a mixture of water with methanol and / or ethanol and / or isopropanol.

5. The method according to any one of claims 1 to 4, characterized in that the light source is a red LED lamp.

6. 5. The method according to any one of claims 1 to 4, characterized in that the light source is a white LED lamp combined with a filter that blocks wavelengths below 500 nm.

7. R ８ =R ８’ =R ８’’ =R ８’’’ =CH ３ The method according to any one of claims 1 to 6, characterized in that:

8. X － 8. The method according to claim 1, wherein represents a halide.

9. 9. The method according to any one of claims 1 to 8, characterized in that the concentration of the compound of formula (II) is in the range of 0.002 to 2.0 mol / l at the start of the photo-oxidation.

10. 10. The method according to any one of claims 1 to 9, characterized in that the ratio of the compound of formula (III) to the compound of formula (II) is in the range of 0.005 to 20 mol %.

11. The method according to any one of claims 1 to 10, characterized in that it is a continuous process.

12. A method for preparing a compound of formula (IV) from a compound of formula (II), a) photo-oxidizing a compound of formula (II) by the method according to any one of claims 1 to 11 to obtain a compound of formula (I): 【Transformation 3】 obtaining a compound of formula (I); b) reducing the compound of formula (I) with a reducing agent to obtain a compound of formula (IV): 【Chemistry 4】 obtaining a compound of formula (I); A method comprising:

13. 13. The method of claim 12, wherein step b) is performed continuously.

14. A method for preparing a compound of formula (V) from a compound of formula (II), a) photo-oxidizing a compound of formula (II) by the method according to any one of claims 1 to 11 to obtain a compound of formula (I): 【Transformation 5】 obtaining a compound of formula (I); b) reducing the compound of formula (I) with a reducing agent to obtain a compound of formula (IV): 【Transformation 6】 obtaining a compound of formula (I); (c) treating the compound of formula (IV) with a basic substance at a temperature of >200° C. to obtain a compound of formula (V): 【Transformation 7】 obtaining a compound of formula (I); A method comprising:

15. 15. The method according to claim 14, characterized in that steps b) and / or c) are carried out continuously.

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