Photooxidation of 2,4,6-trimethylphenol

Abstract

The present invention relates to the photooxidation of 2,4,6-trimethylphenol to obtain 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one, wherein light in the high wavelength range of the visible spectrum is used and methylene blue is used as a photosensitizer in a solvent mixture of water and an alcohol. This method allows the obtaining of 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one and 2,3,5-trimethylhydroquinone from 2,4,6-trimethylphenol in high yield and selectivity.

Description

Technical Field

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

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

[0003] T. Netscher in Vitam. Horm. 2007, 76, 155 - 202, particularly on page 159, and W. Bonrath et al. in Angew. Chem. Int. Ed. 2012, 51, 12960 - 12990, particularly on page 12983, disclose that 2,3,5-trimethylhydroquinone can be obtained from m-cresol, which is catalytically methylated to 2,3,6-trimethylphenol, and then 2,3,6-trimethylphenol is converted to 2,3,5-trimethylbenzoquinone by oxidation and subsequently reduced to 2,3,5-trimethylhydroquinone. An alternative process starts from isophorone and uses an oxidation / hydrogenation / isomerization sequence. A further method is to use mesitol as the starting product and obtain 2,3,5-trimethylhydroquinone using oxidation and rearrangement.

[0004] US 2012 / 0203013 A1 discloses the oxidation of 2,4,6-trimethylphenol (mesitol) with hydrogen peroxide in the presence of a bismuth catalyst. MC et al. in Angew. Chem. Int. Ed. 2006, 45, 2737–2741 disclose that mesitol can be oxidized with oxone in acetonitrile.

[0005] It has been proposed by Murtinho D. et al. in J. Chem. Soc. Perkin Trans. 2, 2000, 2441 - 2447 to use photooxidation of 2,3,5-trimethylphenol with oxygen in the presence of a photosensitizer to obtain 2,3,5-trimethylbenzoquinone. Specifically, it discloses methylene blue as a photosensitizer for 1,5-dihydroxynaphthalene in a mixture of acetonitrile and dichloromethane. However, due to the moderate yield of 78% to 82%, it has been proposed to use porphyrin-type photosensitizers instead. Such porphyrin compounds are quite expensive and not readily commercially available. On the other hand, acetonitrile and dichloromethane are solvents with significant ecological and ecotoxicological drawbacks. In addition, it is known that oxidizing phenols is much more difficult than oxidizing naphthols.

[0006] Unlike 2,3,5 - trimethylphenol, mesitol (=2,4,6 - trimethylphenol) is readily available. It is of great commercial interest to provide a process for manufacturing 2,3,5 - trimethylhydroquinone starting from mesitol instead of m - cresol or 2,3,5 - trimethylphenol, respectively. SUMMARY OF THE INVENTION

[0007] Accordingly, the problem to be solved by the present invention is to provide an efficient process for synthesizing 4 - hydroperoxy - 2,4,6 - trimethylcyclohexa - 2,5 - dien - 1 - one or 4 - hydroxy - 2,4,6 - trimethylcyclohexa - 2,5 - dien - 1 - one or 2,3,5 - trimethylhydroquinone in high yield and selectivity.

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

[0009] In the present invention, methylene blue can be used. Methylene blue is a very attractive photosensitizer that is readily available and cost - effective, and the desired product is obtained not only in very high yield at high conversion but also with very high selectivity. Particularly advantageously, this process can be carried out without any chlorinated solvents. Therefore, the process is very attractive for industrial applications.

[0010] Other aspects of the present invention are the subject of other independent claims. Particularly preferred embodiments are the subject of the dependent claims. DETAILED DESCRIPTION

[0011] The present invention relates in a first aspect to a process for manufacturing a compound of formula (I) from a compound of formula (II) by photo - oxidation, wherein the photo - oxidation is carried out under the following conditions: using oxygen and a photosensitizer of formula (III), in a solvent mixture of water and at least one C 1-8 alkanol or at least one C 2-4 alkylene glycol, and using light having a peak wavelength (λ max ) in the range between 580 nm and 780 nm in its spectrum,

[0012]

[0013]

[0014] wherein R 8 , R 8 ', R 8 ” and R 8 ”' independently of one another represent H or C 1-4 alkyl;

[0015] or

[0016] wherein R 8 and R 8 ' and / or R 8 ” and R 8 ”' together with N form a five- or six-membered ring;

[0017] provided that the residue R 8 、R 8 '、R 8 ” and R 8 ”' is at least one different from H;

[0018] and X - represents an anion.

[0019] For the sake of clarity, some of the terms used in this document are defined as follows:

[0020] In this document, "C x-y alkyl" is an alkyl group containing x to y carbon atoms, that is, for example, C 1-3 alkyl is an alkyl group containing 1 to 3 carbon atoms. The alkyl group can be straight-chain or branched-chain. For example, -CH(CH3)-CH2-CH3 is considered a C4-alkyl.

[0021] Similarly, C x-y alkanol or C x-y alkylene glycol are alcohols having one or two OH groups, respectively, wherein the alcohol has an alkyl or alkylene group containing x to y carbon atoms.

[0022] In the case where there are the same marks for symbols or groups in several formulas, in this document, the definition of the group or symbol made in the context of a specific formula also applies to other formulas containing the same mark.

[0023] The peak wavelength is the wavelength at which the spectrum reaches its maximum intensity.

[0024] In the method, 2,4,6-trimethylphenol (= the compound of formula (II), mesitol) is photooxidized to obtain 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (= the compound of formula (I)).

[0025] Mesitol is a known chemical, which can be purchased in large quantities from different suppliers and can be easily produced, for example, by the reaction of mesitylene with permonophosphoric acid.

[0026] In the photooxidation, a photosensitizer of formula (III) is used

[0027]

[0028] wherein R 8 、R 8 ', R 8 ” and R 8 ”' independently represent H or C 1-4 alkyl;

[0029] or

[0030] wherein R 8 and R 8 ' and / or R 8 ” and R 8 ”' together with N form a five - or six - membered ring;

[0031] provided that at least one of the residues R 8 、R 8 ', R 8 ” and R 8 ”' is different from H;

[0032] and X - represents an anion.

[0033] 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 -.

[0034] More preferably, R 8 = R 8 ”, and / or R 8 ' = R 8 ”'. More preferably, R 8 = R 8 ' = R 8 ” = R 8 ”'.

[0035] More preferably, the substituents R 8 、R 8 ', R 8 ” and R 8 ”' represent C 1-4 alkyl, even more preferably R 8 = R 8 ' = R 8 ” = R 8 ”' = methyl or ethyl.

[0036] Most preferably, R 8 = R 8 ' = R 8 ” = R 8 ”' = CH3.

[0037] In formula (III), X - represents an anion. The role of the anion is to balance the charge of the cation represented by the part within the parentheses ([)(]) in the above formula. Therefore, in principle, any anion can be used.

[0038] Preferably, X - represents a halide ion, most preferably a chloride ion.

[0039] Preferably, the compound of formula (III) is methylene blue. Further preferably, the compound of formula (III) is in the form of a double salt with zinc chloride, especially the double salt of methylene blue and zinc chloride, or the compound of formula (III) is in the form of a hydrate, preferably methylene blue hydrate (CAS: 122965 - 43 - 9).

[0040] It has been found that the photosensitizer of formula (III) is particularly suitable for the photo - oxidation of the compound of formula (II).

[0041] Importantly, for the above photo - oxidation, the light used has a peak wavelength (λ max ) within the range between 580 nm and 780 nm in its spectrum.

[0042] In a preferred embodiment, light having a peak wavelength (λ max ) within the range between 585 nm and 625 nm in its spectrum is used. This corresponds to light that is perceived as orange.

[0043] In another more preferred embodiment, light having a peak wavelength (λ max ) within the range between 625 nm and 740 nm in its spectrum is used. This corresponds to light that is perceived as red.

[0044] This light mainly has a high - wavelength range of the visible spectrum.

[0045] In another preferred embodiment, the light used is characterized in that more than 80% of the light has a wavelength between 525 nm and 780 nm, preferably more than 80% of the light has a wavelength between 525 nm and 700 nm, and more preferably more than 65% of the emitted light has a wavelength between 550 nm and 650 nm.

[0046] In another preferred embodiment, the light used is characterized in that more than 80% of the light has a wavelength between 550 nm and 780 nm, preferably more than 80% of the light has a wavelength between 600 nm and 760 nm, more preferably more than 65% of the emitted light has a wavelength between 625 nm and 700 nm, and even more preferably more than 85% of the emitted light has a wavelength between 625 nm and 700 nm.

[0047] Therefore, it is important that the light used does not have a large amount of light with wavelengths below 580 nm in its spectrum. It is important that it has been found that green, blue and purple light or light having a significant amount of green, blue and purple in its spectrum is not suitable for the above-mentioned photooxidation.

[0048] In one embodiment, the light for photooxidation can be achieved by filtering out the unwanted light wavelengths from the light source. For example, a light source with polychromatic or white light emission can be filtered by a filter that blocks the unwanted wavelengths.

[0049] Using different physical methods for filtering light, there are different possibilities for such known and commercially available filters, such as absorption filters, dichroic filters, monochromatic filters, band-pass filters, short-pass filters or wedge filters.

[0050] Particularly useful are absorption filters or cut-off filters.

[0051] Particularly preferably, the light source is a combination of a white LED lamp and a filter that blocks wavelengths below 500 nm, more particularly below 625 nm.

[0052] A red LED lamp is the most preferred light source for the light.

[0053] Figure 1a A schematic diagram showing this embodiment. The light source (1) emits radiation of different wavelengths, which has desired wavelengths (2a) and unwanted wavelengths (2b). The light source is preferably white light, more preferably a white LED. The filter (6) is located between the light source (1) and the photoreactor with a transparent wall (4). The filter (6) filters out the light of unwanted wavelengths to provide light having a peak wavelength (λ max ) between 580 nm and 780 nm in its spectrum. The filter (6) is preferably an "orange filter" or a "red filter", that is, a filter that only allows light with wavelengths between 585 nm and 625 nm or between 625 nm and 740 nm to pass through. The reaction mixture (3) containing at least oxygen and the compound of formula (II) as well as water and at least one C 1-8 alkanol or at least one C 2-4 alkylene glycol solvent mixture is inside the photoreactor (5).

[0054] By a photoreaction, the compound of formula (I) is produced by a photochemical reaction from the compound of formula (II) and oxygen, especially in a gas mixture containing at least 20% by volume of oxygen.

[0055] A specific preferred example of this embodiment is a white LED. Its light is filtered in such a way that all light not having the desired wavelength is blocked or at least significantly absorbed (e.g., using an "orange filter" (allowing only light between 585 nm and 625 nm to pass through) or a "red filter" (allowing only light between 625 nm and 740 nm to pass through)).

[0056] Therefore, the light source for the light is preferably a combination of a white LED lamp and a filter that blocks wavelengths below 500 nm, especially below 625 nm.

[0057] In another embodiment, the light for the photooxidation can be generated by a corresponding light source that emits light having the desired wavelength.

[0058] Figure 1b A schematic diagram representing this embodiment. The light source (1) emits radiation of the desired wavelength (2a) to provide light having a peak wavelength (λ max ) in the range between 580 nm and 780 nm in its spectrum. The light source is preferably orange light or red light, more preferably an orange or red LED, to provide light using light having a peak wavelength (λ max ) in the range between 580 nm and 780 nm in its spectrum.

[0059] A reaction mixture (3) containing at least oxygen and the compound of formula (II) as well as water and at least one C 1-8 alkan-ol or at least one C 2-4 alkylene diol solvent mixture is inside the photoreactor (5). By a photoreaction, the compound of formula (I) is produced by a photochemical reaction from the compound of formula (II) and oxygen.

[0060] Specific examples of the light source for this embodiment are red LEDs or red or orange lasers, preferably red or orange LED lamps. Red and orange LED lamps are widely commercially available. Red and orange LEDs can provide high-intensity red light or orange light. In a preferred embodiment, a flexible strip can be used, which has a plurality of individual LEDs incorporated in the strip. This allows ensuring the radial orientation of the LEDs around a curved surface (such as a transparent tube), for example, by simply winding the strip around the tube, preferably in a helical manner.

[0061] The photooxidation is carried out in water and at least one C 1-8in a solvent mixture of an alkanol or at least one C 2-4 alkylene glycol is carried out.

[0062] C 1-8 The alkanol is preferably selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, heptanol, and hexanol, and more preferably selected from the group consisting of methanol, ethanol, and isopropanol.

[0063] C 2-4 The alkylene glycol 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 preferably selected from the group consisting of ethane-1,2-diol, propane-1,2-diol, and propane-1,3-diol.

[0064] Preferably, the solvent mixture is water and at least one C 1-8 alkanol or at least one C 2-4 alkylene glycol mixture, forming a homogeneous phase.

[0065] Preferably, the solvent mixture is water and at least one C 1-8 alkanol or at least one C 2-4 alkylene glycol mixture. More preferably, the solvent mixture is water and C 1-8 alkanol mixture.

[0066] Even more preferably, the solvent mixture is water and C 1-6 alkanol mixture.

[0067] More preferably, the solvent mixture is water and a mixture of methanol and / or ethanol and / or isopropanol. More preferably, the solvent mixture is water and a mixture of methanol and / or ethanol.

[0068] Preferably, the volume ratio of water to the sum of C 1-8 alkanol and C 2-4 alkylene glycol is in the range of between 1:10 and 1:1, particularly between 1:5 and 1:2.

[0069] In a very preferred embodiment, the solvent mixture is water and methanol, and preferably the volume ratio of water to methanol ranges from 1:20 to 1:2, preferably 1:10 to 1:2, more preferably 1:6 to 1:3, and most preferably 1:4.

[0070] A key advantage of the present invention is that photooxidation is carried out in a mixture of water and at least one C 1-8 alkanol or at least one C 2-4It is carried out in a solvent mixture composed of alkylene glycols, and the solvents are very suitable solvents both ecologically and ecotoxicologically and are also economically advantageous. Therefore, it is very advantageous that the above method is carried out in the absence of any chlorinated solvents.

[0071] Preferably, at the start of photooxidation, the concentration of the compound of formula (II) is in the range of between 0.002 mol / l and 2.0 mol / l, preferably between 0.01 mol / l and 0.2 mol / l.

[0072] More preferably, the ratio of the compound of formula (III) to the compound of formula (II) is in the range of between 0.005 mol% and 20 mol%, preferably between 0.05 mol% and 20 mol%, more preferably between 0.2 mol% and 10 mol%.

[0073] In one embodiment, oxygen is used in the form of a mixture containing oxygen and an inert gas. Preferably, in this mixture containing oxygen and an inert gas, the amount of oxygen is at least 15% by volume, especially at least 20% by volume. Such a mixture can be, for example, a binary mixture, such as an oxygen / nitrogen or oxygen / argon mixture, etc. The mixture can consist of two or more inert gases or contain two or more inert gases. Particularly preferably, air is used as this mixture containing oxygen and an inert gas.

[0074] In a preferred embodiment, oxygen is used in a substantially pure form, i.e., the amount of oxygen in the gas is 90% - 100%, more preferably 95% - 100%, even more preferably 99% - 100%.

[0075] Photooxidation can be carried out at ambient pressure or under pressure. Preferably, the oxidation is carried out under pressure, especially at a pressure greater than 2 bar, preferably greater than 3 bar, more preferably between 2 bar and 20 bar.

[0076] Photooxidation is carried out in a suitable photoreactor. Preferred photoreactors are flow reactors, especially spiral flow reactors.

[0077] The individual components can be introduced into the photoreactor separately or as a mixture. Preferably, the reaction mixture is prepared before entering the photoreactor.

[0078] In one of the preferred embodiments, an oxygen-containing solvent mixture is admixed with the compound of formula (II) before entering the photoreactor.

[0079] In another preferred embodiment, the solvent mixture is admixed with the compound of formula (II) already containing oxygen before entering the photoreactor.

[0080] In the most preferred embodiment, oxygen is added to a premix comprising at least the compound of formula (II) and a solvent mixture.

[0081] The reaction is preferably carried out in such a way that the pressure of oxygen is controlled by a suitable valve and a mass flow controller. Such process control equipment and methods for photoreactions using liquids and gases are known to those skilled in the art.

[0082] Preferably, the photooxidation is carried out in a reactor allowing a continuous process, since preferably the method is a continuous method.

[0083] By this photooxidation process (step a)), 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (I)) can be obtained in very high yields, preferably above 95%, even more preferably above 98% and with very high selectivity.

[0084] On the other hand, the present invention relates to a method for preparing a compound of formula (IV) from a compound of formula (II), comprising the following steps:

[0085] a) Photooxidation of the compound (II) as described in detail above to produce a compound of formula (I);

[0086]

[0087] b) Reduction of the compound of formula (I) by means of a reducing agent to obtain a compound of formula (IV)

[0088]

[0089] In order to reduce the compound of formula (I) in step b), a variety of reducing agents can be used.

[0090] Suitable reducing agents can be thiosulfates, trialkylamines, tertiary phosphines, hydrogen, dithionites, sulfites, trialkyl phosphites, iodides, metals or dialkyl sulfides.

[0091] 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).

[0092] Preferably used as a reducing agent is a thiosulfate, especially sodium thiosulfate.

[0093] Preferably, the reducing agent is used in a significant molecular excess, most preferably in an amount between 2 and 10 equivalents relative to the compound of formula (I). Further preferably, the reduction is carried out in an aqueous alcohol, particularly at room temperature.

[0094] The reduction is indicated by a color change to pink.

[0095] The reduction of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (I)) is carried out on a quantitative scale, and 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (compound of formula (IV)) can be obtained in a yield greater than 90%, preferably greater than 92%.

[0096] The reduction in step b) can be carried out in a batch process or a continuous process.

[0097] Preferably, step b) is carried out in a continuous manner.

[0098] For example, the addition of the reducing agent can be carried out at the end of the photoreactor as described above. In addition, preferably, the reduction of step b) is carried out in a flow reactor.

[0099] Figure 4a and Figure 4b More details of these embodiments are shown.

[0100] In another aspect, the present invention relates to a method for preparing a compound of formula (IV) from a compound of formula (II), comprising the following steps:

[0101] a) Photooxidation of compound (II) as described in detail above to produce a compound of formula (I);

[0102]

[0103] b) Reduction of the compound of formula (I) by means of a reducing agent to obtain a compound of formula (IV)

[0104]

[0105] c) Treating the compound of formula (IV) with a basic substance at a temperature > 200 °C, preferably > 240 °C, to obtain a compound of formula (V)

[0106]

[0107] Steps a) and b) have been discussed in great detail above. Figure 6 The reaction sequence of steps a), b) and c) is schematically shown.

[0108] In step c), the compound of formula (IV) is treated with a basic substance at a temperature of > 200 °C, preferably > 240 °C, to obtain the compound of formula (V).

[0109] Particularly suitable as such basic substances are 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. As examples of such basic substances, the following compounds are mentioned:

[0110] A. Hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, etc.; and

[0111] B. Carbonates and hydrogencarbonates of alkali metals or alkaline earth metals, such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, barium carbonate and magnesium carbonate; and

[0112] C. Oxides of alkaline earth metals, such as calcium oxide, magnesium oxide, barium oxide, etc.; and

[0113] D. Compounds containing alkali metals or alkaline earth metals which have hitherto been used as buffers, such as a suitable mixture of an alkali metal dihydrogenphosphate (such as potassium dihydrogenphosphate) and a disodium hydrogenphosphate (such as disodium hydrogenphosphate), or alkali metal salts of organic carboxylic acids such as boric acid, citric acid, lactic acid, tartaric acid and acetic acid.

[0114] Preferably, step c) is carried out in the presence of water. More preferably, in step c) there is also at least one water-soluble alcohol present in addition to water, preferably methanol and / or ethanol and / or isopropanol.

[0115] Step c) is preferably carried out in the presence of a basic substance such that the pH is not less than 6.5, preferably not less than 7. A most preferred pH of the reaction mixture is 7 - 14.

[0116] Preferably, step c) is carried out under reducing conditions or under an inert atmosphere, especially under nitrogen or argon. Step c) is preferably carried out in the presence of a reducing substance. Examples of such a reducing substance are sodium sulfite (Na2SO3), sodium bisulfite (NaHSO3), sodium dithionite (Na2S2O4) and sodium thiosulfate (Na2S2O3).

[0117] Preferably, at the end of the reaction, the basic reaction mixture is neutralized by means of an acid.

[0118] Preferably, reaction step c) is carried out as disclosed in US 3,957,887, especially as described in its Example 12.

[0119] The reaction in step c) can be carried out in a batch process or a continuous process.

[0120] Preferably, step c) is carried out in a continuous manner.

[0121] 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 directly further reacted to form the compound of formula (V) using the appropriate conditions in the reduction step b). However, preferably, step c) is carried out after step b) occurs, preferably after step b) is completely carried out.

[0122] Preferably, step c) is carried out in a flow reactor.

[0123] Preferably, step c) is carried out in such a flow reactor that is placed after the flow reactor in which step b) is carried out. In another embodiment, the reaction of step b) occurs at the downstream end of the continuous reactor in which the reaction step b) occurs.

[0124] In an even further embodiment, reaction steps a), b) and c) are all carried out in a single flow reactor, where photooxidation (step a)) occurs first, then the reduction of step b) occurs downstream, and the reaction step occurs further downstream.

[0125] Figure 5a and Figure 5b and Figure 5c shows more details of these embodiments.

[0126] The present invention shows that 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one or 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one or 2,3,5-trimethylhydroquinone can be obtained in high yield and selectivity. In particular, it can be demonstrated that these substances can be obtained in high yield and selectivity in all mesitol-based processes. It can be shown that 2,3,5-trimethylhydroquinone can be obtained from mesitol with an overall yield (steps a), b), c)) of more than 84%. BRIEF DESCRIPTION OF THE DRAWINGS

[0127] Figure 1a Shows a schematic diagram of photooxidation using a light source and a filter that produces light having a peak wavelength (λ max ) between 580 nm and 780 nm in its spectrum.

[0128] Figure 1b Shows a schematic diagram of photooxidation using a light source having a peak wavelength (λ max ) between 580 nm and 780 nm in its spectrum.

[0129] Figure 2a Shows a schematic diagram of one of the experimental layouts.

[0130] Figure 2b Shows a schematic diagram of a different experimental layout.

[0131] Figure 2c Shows a schematic diagram of another different experimental layout.

[0132] Figure 3 Represents the light used for photooxidation with different filters in the experiment and the normalized emission spectra of white light and red LEDs.

[0133] Figure 4a Shows a schematic diagram of the continuous reactor of step b).

[0134] Figure 4b Shows a schematic diagram of an embodiment in which step b) is carried out at the end of the photoreactor of step a).

[0135] Figure 5a Shows a schematic diagram of the continuous reactor of step c).

[0136] Figure 5b Shows a schematic diagram of an embodiment in which steps c) and b) are carried out at the end of the photoreactor of step a).

[0137] Figure 6 Shows a schematic overview of the reaction scheme of steps a), b) and c).

[0138] In Figure 2a a preferred experimental layout is shown. A container containing the premix (10) is pumped into the photoreactor (5) by a pump (7), and the premix (10) contains at least a compound of formula (II) and a photosensitizer of formula (III) as well as a solvent mixture of water and at least one C 1-8 alkanol or at least one C 2-4 alkylene glycol. Before entering the photoreactor (5), oxygen (11), preferably in the form of air, is admixed to the premix to form a photooxidation reaction mixture (3). The amount of oxygen admixed is controlled by a mass flow controller (8). A light source (1), particularly in a spiral arrangement of LEDs, is arranged around the transparent wall (4) of the linear tubular photoreactor (5). In one embodiment, the light source (1) is a white LED. A filter (6) is positioned between the transparent wall (4) and the light source (1) to allow light to be provided with a peak wavelength (λ max) light (2a). The filter (6) is in particular an orange filter or a red filter, in particular to provide a peak wavelength (λ in its spectrum in the range between 585 nm and 625 nm or between 625 nm and 740 nm respectively max ) light. In another preferred embodiment, the light source (1) is an orange LED or a red LED, in particular a red LED, in which case there is no filter (6). The photoreactor (5) is preferably a spiral flow reactor. A back pressure regulator (9) is located at the outlet of the photoreactor before the product is collected in the collection container (12).

[0139] This experimental setup, in particular the combination of the light source and the photoreactor, is preferably used for photoreactions of larger volumes.

[0140] In Figure 2b , another preferred experimental setup is shown. The container containing the premix (10) is pumped into the photoreactor (5) by a pump (7), and the premix (10) contains at least the compound of formula (II) and the photosensitizer of formula (III) as well as a solvent mixture of water and at least one C 1-8 alkan-ol or at least one C 2-4 alkylene glycol. Before entering the photoreactor (5), oxygen (11) is admixed into the premix to form a photooxidation reaction mixture (3). The amount of the admixed oxygen is controlled by a mass flow controller (8).

[0141] In one embodiment, the light source (1) is a white LED. A filter (6) is located between the transparent wall (4) of the photoreactor (5) and the light source (1), so as to allow light (2a) to be provided with a peak wavelength (λ in its spectrum in the range between 580 nm and 780 nm max ). In this illustration, only one light source (1) and one filter (6) are shown. Of course, it is possible that several such combinations of light sources (1) and filters (6) are located around the photoreactor (5) in the form of a spiral flow reactor, and can be positioned to allow uniform irradiation of the entire photoreactor (5). The filter (6) is in particular an orange filter or a red filter, in particular to provide a peak wavelength (λ in its spectrum in the range between 585 nm and 625 nm or between 625 nm and 740 nm respectively max ). Light (2b) with an undesired wavelength is filtered out by the filter (6). In another preferred embodiment, the light source (1) is an orange LED or a red LED, more preferably a red LED, in which case there is no filter (6). A back pressure regulator (9) is located at the outlet of the photoreactor before the product is finally collected in the collection container (12).

[0142] This experimental setup, particularly the combination of the light source and the photoreactor, is preferably used for photoreactions of smaller volumes.

[0143] In Figure 2c , another preferred experimental setup is shown. A container containing the premix (10) is pumped into the photoreactor (5) by a pump (7), and the premix (10) contains at least the compound of formula (II) and the photosensitizer of formula (III), as well as a solvent mixture of water and at least one C 1-8 alkan-ol or at least one C 2-4 alkylene glycol. Before entering the photoreactor (5), oxygen (11), preferably in the form of air, is admixed into the premix to form a photooxidation reaction mixture (3). The amount of the admixed oxygen is controlled by a mass flow controller (8).

[0144] In this embodiment, the light source (1), preferably a red LED, is arranged in the hollow space formed by the helical winding of the helical flow reactor (5).

[0145] In one embodiment, the light source (1) is a white LED. Around the light source (1), that is, between the transparent wall (4) of the photoreactor (5) and the light source (1), a filter (6) is positioned to allow light (2a) with a peak wavelength (λ max ) within the range of between 580 nm and 780 nm in its spectrum to be provided. The filter (6) is particularly an orange filter or a red filter, preferably a red filter, to particularly provide light with peak wavelengths (λ max ) within the range of between 585 nm and 625 nm or between 625 nm and 740 nm respectively in its spectrum. Light (2b) with undesired wavelengths is filtered out by the filter (6). In another preferred embodiment, the light source (1) is an orange LED or a red LED, preferably a red LED, and in this case, there is no filter (6). A back-pressure regulator (9) is positioned at the outlet of the photoreactor before the product is finally collected in the collection container (12).

[0146] This experimental setup, particularly the combination of the light source and the photoreactor, is preferably used for photoreactions of smaller volumes.

[0147] In an even further embodiment, Figure 2b ) and Figure 2c ) the light source (1) and the filter (6) are combined. In other words, the filter and the light source can be arranged outside the wall of the photoreactor, and the wall of the photoreactor is arranged inside and outside the space formed by the helical winding of the helical flow photoreactor (5).

[0148] InFigure 4a shows a preferred experimental layout for reaction step b), which allows the reduction of the compound of formula (I) to be carried out in a continuous manner. The compound of formula (I) (13) is transferred into the reactor (14) for reduction by means of a pump (7), and the reducing agent (15) is also added into the reactor (14) for reduction by means of the pump (7). In a variant layout of this layout, the addition of the compound of formula (I) and the reducing agent is achieved before the compound of formula (I) enters the reactor (14). When using other ingredients ( Figure 4a not shown in) for reduction, the additional ingredients can be added to the reducing agent (15) or the compound of formula (I) (13) or fed separately into the reduction reactor (14). In the reactor (14) for reduction, the compound of formula (I) is reduced to the compound of formula (IV), and the compound of formula (IV) is transferred from the reactor to the collection container (12) for the compound of formula (IV).

[0149] In Figure 4b shows a more preferred experimental layout for reaction steps a) and b), which allows the photoreaction of mesitol and the reduction of the compound of formula (I) to be carried out in a continuous manner. In the shown embodiment, it basically corresponds to the combination of the representations shown in Figure 2c and Figure 4a . However, in this embodiment, the compound of formula (I) is directly transferred from the outlet of the photoreactor (5) to the inlet of the reactor for reducing the compound of formula (I) to the compound of formula (IV).

[0150] In Figure 5a shows a preferred experimental layout for reaction step c). The compound of formula (IV) (16) is transferred into the reactor (17) for heat treatment by means of a pump (7), and the basic substance (18) is also added into the reactor (17) for heat treatment by means of the pump (7). In a variant layout of this layout, the addition of the compound of formula (IV) and the basic substance is achieved before the compound of formula (IV) enters the reactor (17). When using other ingredients ( Figure 5a not shown in) for heat treatment, the additional ingredients can be added to the basic substance (18) or the compound of formula (IV) (16) or fed separately into the reactor (17) for heat treatment.

[0151] In the reactor (17) for heat treatment, the compound of formula (IV) is transformed into the compound of formula (V), and the compound of formula (V) is transferred from the reactor to the collection container (12) for the compound of formula (V).

[0152] In Figure 5bFigure 0 shows a more preferred experimental layout for reaction steps a), b) and c), which allows for the photoreaction of mesitol, the reduction of the compound of formula (I), and the heat treatment of the compound of formula (IV) all to be carried out in a continuous manner. In the illustrated embodiment, it substantially corresponds to Figure 4b and Figure 5a the combination of representations shown in. 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 heat treating the compound of formula (IV) to the compound of formula (V).

[0153] List of reference signs

[0154] 1 Light source

[0155] 2a Light with a desired wavelength

[0156] 2b Light with an undesired wavelength

[0157] 3 Photooxidation reaction mixture

[0158] 4 Transparent wall of the photoreactor

[0159] 5 Photoreactor

[0160] 6 Filter

[0161] 7 Pump

[0162] 8 Mass flow controller

[0163] 9 Back pressure regulator

[0164] 10 Premix

[0165] 11 Oxygen

[0166] 12 Collection container

[0167] 13 Compound of formula (I)

[0168] 14 Reactor for reduction

[0169] 15 Reducing agent

[0170] 16 Compound of formula (IV)

[0171] 17 Reactor for heat treatment

[0172] 18 Basic substance

[0173] Examples

[0174] The present invention is further illustrated by the following experiments.

[0175] Example 1: Photooxidation of 2,4,6-trimethylphenol (Step a)

[0176] In the following experiments, the experimental layout schematically shown in Figure 2c was used:

[0177] A container (10) containing a premix of a solvent or solvent mixture, a substance to be photo-oxidized, and a photosensitizer is pumped by a pump (7) into a photoreactor (5), which is a helical flow reactor. Before entering the photoreactor (5), oxygen (11) in the form of air is admixed to the premix to form a photo-oxidation reaction mixture (3). The amount of air admixed is controlled by a mass flow controller (8). The light of the light source (1) is a red LED (12x SSL Hyper red, λ max = 660 nm, about 9 W & 700 lm for 12 LEDs, GH CSSPM1.24, 120° viewing angle, CPU cooling system (10V) to maintain the ambient temperature (about 20 °C)) (no filter is used) (see the spectrum shown as LSr in Figure 3 ), and as a result, light of the desired wavelength (2a) falls on the transparent wall (4) of the photoreactor (5). The photoreactor (5) is wound around an internal glass cylinder of the LED lamp (1) and cooled by a fan. A back-pressure regulator (9) is positioned at the outlet of the photoreactor before the product is finally collected in a container (12).

[0178] More precisely, the photo-oxidation is carried out as follows:

[0179] A solution of 2,4,6-trimethylphenol (20.0 mmol·L -1 , 2.00 mmol [during the reaction], 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) is prepared to obtain a homogeneous blue solution. The solution is pumped into the photoreactor (pipe system: 0.75 mm inner diameter, 1.58 mm outer diameter, PFA coil) by a high-pressure liquid chromatography pump (Dionex P580) (liquid flow rate: 0.093 mL / min, HPLC regulating piston pump) with a constant pressure of 10 bar (regulated by a back-pressure regulator, Equilibar Zero-Flow ZF1 back-pressure regulator, computer-controlled).

[0180] Before entering the photoreactor, the solution was flushed 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). Inside the photoreactor, the reaction mixture was exposed to a red LED light source (12x SSLHyper red, λ max = 660 nm, approximately 15 W & 700 lm for 12 LEDs, GH CSSPM1.24, 120° viewing angle) (see Figure 3 the spectrum shown as LSr). Complete conversion was confirmed by thin layer chromatography (4:1 cyclohexane / EtOAc, R f (substrate) = 0.63, R f (product) = 0.3). The photoreactor was maintained at ambient temperature (20 °C) by 2 vans (one inside the photoreactor: CPU cooling system, one outside the photoreactor: ordinary van). 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 until a constant residue (15 mbar) was obtained. Water (50 mL) was added to the residue and the solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the organic solvents were removed under reduced pressure (15 mbar) to give 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one as a greenish-grey viscous wax (340 mg, 99% yield).

[0181] Example 2: Reduction of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (Step b)

[0182] In a 50 mL round-bottom flask, a yellow solution of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (300 mg, 1.78 mmol, 1.0 equivalent) and sodium thiosulfate (1.40 g, 8.90 mmol, 5.0 equivalents) in methanol and water (25 mL, 4:1 v / v) prepared as in Example 1 was prepared. The reaction mixture was stirred at ambient temperature until complete conversion was monitored by thin layer chromatography (4:1 cyclohexane / EtOAc, R f (substrate) = 0.3, R f(Product) = 0.2). The color of the solution was observed to change from yellow to pink. Methanol was removed under reduced pressure. Water (30 mL) was added to the residue and the solution was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the organic solvents were removed under reduced pressure (15 mbar) to afford 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one as a yellow-green viscous wax (253 mg, 93% yield).

[0183] Example 3: Formation of 2,3,5-trimethylhydroquinone (Step c)

[0184] In the following experiment, the experimental layout schematically represented as in Figure 5a was used:

[0185] At 250 °C at 10 ml / min, 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). 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 preparing a compound of formula (I) from a compound of formula (II) by photooxidation, wherein the photooxidation is carried out under the following conditions: Using oxygen and a photosensitizer of formula (III), in a solvent mixture of water and at least one C 1-8 alkan-ol or at least one C 2-4 alkylene diol, and using light having a peak wavelength (λ max ) in the range between 580 nm and 780 nm in its spectrum, wherein R 8 , R 8' , R 8” and R 8”' each independently represents H or C 1-4 alkyl; Or wherein R 8 and R 8' and / or R 8” and R 8”' together with N form a five- or six-membered ring; The prerequisite is that residue R 8 , R 8' , R 8” and R 8”' is different from H in at least one of them; And X - represents an anion.

2. The method according to claim 1, wherein The light used has a peak wavelength (λ max ) in its spectrum in the range between 625 nm and 740 nm.

3. The method according to any one of the preceding claims, characterized in that, More than 80% of the light has a wavelength between 525 nm and 780 nm.

4. The method according to any one of the preceding claims 1 and 2, characterized in that The solvent mixture is a mixture of water and methanol and / or ethanol and / or isopropanol.

5. The method according to any one of the preceding claims 1 and 2, characterized in that, The light source for the light is a red LED lamp.

6. The method according to any one of the preceding claims 1 and 2, characterized in that The light source for the light is a combination of a white LED lamp and a filter that blocks wavelengths below 500 nm.

7. The method according to any one of the preceding claims 1 and 2, characterized in that, R 8 = R 8' = R 8” = R 8”' = CH3.

8. The method according to any one of the preceding claims 1 and 2, characterized in that, X - represents a halogen ion.

9. The method according to any one of the preceding claims, characterized in that, At the start of the photooxidation, the concentration of the compound of formula (II) is between 0.002 mol / l and 2.0 mol / l.

10. The method according to any one of the preceding claims 1 and 2, characterized in that The ratio of the compound of formula (III) to the compound of formula (II) is between 0.005 mol% and 20 mol%.

11. The method according to any one of the preceding claims 1 and 2, wherein The method is a continuous method.

12. A method for preparing a compound of formula (IV) from a compound of formula (II), comprising the following steps: a) Photooxidation of the compound (II) according to any one of the preceding claims 1 to 11 to produce a compound of formula (I); b) Reducing the compound (red-a) of formula (I) by means of a reducing agent to obtain a compound of formula (IV) 13. The method according to claim 12, wherein Step b) is carried out in a continuous manner.

14. A method for preparing a compound of formula (V) from a compound of formula (II), comprising the following steps: a) Photooxidation of the compound (II) according to any one of the preceding claims 1 to 11 to produce a compound of formula (I); b) Reducing the compound of formula (I) by means of a reducing agent to obtain a compound of formula (IV) c) Treating the compound of formula (IV) with a basic substance at a temperature > 200 °C to obtain a compound of formula (V) 15. The method according to claim 14, wherein Step b) and / or c) is carried out in a continuous manner.

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