Synthesis of Chromanol Derivatives

Abstract

The present invention relates to a method for preparing chromanol derivatives, in particular to a method for preparing compounds of general formula I, wherein R 1 , R 2 and R 3 are independently selected from hydrogen and methyl, R 4 is selected from C1-C6-alkyl, and X is selected from C1-C 20 -alkyl and C2-C 20 -Alkenyl.

Description

[0001] The present invention relates to a method for preparing chromanol derivatives, and in particular to a method for preparing compounds belonging to the vitamin E family. Background of the Invention

[0003] Vitamin E is the most important fat-soluble antioxidant in biological systems. The term "vitamin E" includes all tocol and tocotrienol derivatives having the biological activity of (2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chroman-6-ol (I.1), which is the vitamin E most relevant to human health (see, for example, W. Bonrath et al., Angew. Chem. Int. ed., 2012, 51, 12960-12990; T. Netscher, Vitamins and Hormons, 2007, Elsevier Inc. volume 76, 155).

[0004] Naturally occurring vitamin E includes tocopherol compounds of formulae 1.1 to 1.4 (α-, β-, γ- and δ-tocopherol) and tocotrienol compounds of formulae 1.5 to 1.8 (α-, β-, γ- and δ-tocotrienol).

[0005]

[0006]

[0007] These naturally occurring compounds exist in the form of single isomers, i.e., α-, β-, γ- and δ-tocopherols (I.1 to I.4) have 2R, 4R, 8R configurations, whereas the corresponding α-, β-, γ- and δ-tocotrienols (I.5 to I.8) exist in the form of 2R, 3E, 7E isomers.

[0008] Industrially, α-tocopherol is mainly prepared in the form of all-racemic α-tocopherol (all-rac I.1a) and all-racemic α-tocopheryl acetate (all-rac-I.1a), which represent an equimolar mixture of all 8 possible stereoisomers. Generally, as shown in Scheme 1, all-racemic α-tocopherol is synthesized by condensation of trimethylhydroquinone (III.1) and all-rac-isophytol. The condensation reaction involves Friedel-Crafts alkylation of trimethylhydroquinone (III.1) followed by a subsequent ring closure reaction. The all-racemic α-tocopherol (all-rac-I.1, all-rac-I.1) thus obtained is then converted into a more stable acetate form (all-rac-I.1a, all-rac-I.1a) by esterification with acetic anhydride.

[0009] Scheme 1: Industrial synthesis of fully racemic α-tocopherol (acetate).

[0010]

[0011] The other tocopherols, ie, beta-, gamma- and delta-tocopherol, and the corresponding tocotrienols, especially alpha-tocotrienol, are generally prepared in an analogous manner.

[0012] In the past decades, many methods for the preparation of α-tocopherol have been developed. An important step in these methods is the Friedel-Crafts alkylation of the corresponding hydroquinone precursor as shown in Scheme 1, which is carried out in the presence of a Friedel-Crafts catalyst.

[0013] Typically, for the Friedel-Crafts reaction, strong Lewis acids such as zinc chloride, aluminum chloride, tin chloride, iron chloride, titanium tetrachloride or boron trifluoride etherate, and combinations of strong Lewis acids with strong Bronsted acids such as hydrochloric acid, sulfuric acid and phosphoric acid are used as catalysts.

[0014] For example, WO 9728151 describes the reaction of 2,3,5-trimethylhydroquinone with isophytol to α-tocopherol by using homogeneous Bronsted and Lewis acids, such as orthoboric acid, oxalic acid, tartaric acid, citric acid or boron trifluoride etherate, in the presence of a cyclic carbonate solvent at elevated reaction temperatures of 145 to 155°C.

[0015] However, the use of these catalysts is associated with several disadvantages. First, they can promote the formation of by-products (for example, the use of oxalic acid, tartaric acid or citric acid generally increases the formation of unwanted phytodienes). In addition, due to their instability towards water, these catalysts generally cannot be recovered and reused. In addition, these catalysts are used in stoichiometric amounts or at high catalytic loadings. Moreover, these catalysts are generally corrosive and waste containing heavy metals (such as zinc or tin) and chlorides is obtained.

[0016] To overcome these disadvantages, heterogeneous catalysts have been used as catalysts for Friedel-Crafts alkylation reactions.

[0017] For example, Odinokov et al., ARKIVOC 2003, (xiii), 101-118 and Scegolev et al., UDK: 547.814.I.07 1982, VINITI 7.09.82, No. 4780-82 describe the use of zeolite catalysts such as Tseokar-10 or ASNC-ZP in the reaction of hydroquinone compounds with tertiary isoprenoid allyl alcohols. The use of zeolites has the disadvantage that the reaction must be carried out at high dilution and these zeolites are generally not commercially available.

[0018] Y.Tachibana, Bull.Chem.Soc.Japan, 1977, 50 (9), 2477 describes the use of zinc chloride or tin chloride treated strongly acidic ion exchange resins (e.g. amberlyst 15) as the catalyst in the reaction of trimethylhydroquinone and isophytol. However, these catalysts usually have the problem of low catalytic activity and produce wastes containing heavy metals and chlorides.

[0019] EP 677520 A1 and Matsui et al., Bull. Chem. Soc. Japan, 1996, 69, 137 describe the use of ion-exchanged bentonite, montmorillonite or saponite treated with scandium chloride or other metal salts (e.g. yttrium, lanthanum, etc.) as catalysts in the reaction of trimethylhydroquinone with isophytol, which has the disadvantage of requiring large amounts of catalyst.

[0020] DE 2404621 has described a kind of solid acid catalyst with specific acid strength by using trimethylhydroquinone and phytol, isophytol or its derivatives reaction to prepare the method for alpha-tocopherol.Wherein, mention the naturally occurring mineral with acidity, for example acid clay, bentonite, kaolin or mordenite, as suitable catalyst.In a specific embodiment, use bentonite as catalyst, obtain required alpha-tocopherol with 51.8% yield.Equally at this, need a large amount of catalysts and the yield obtained is medium. Summary of the invention

[0021] Therefore, the object of the present invention is to provide a method for preparing chromanol derivatives, in particular to provide a method for preparing compounds belonging to the vitamin E family in esterified form, which is effective and provides the desired product in high yield and selectivity without the use of expensive, corrosive and / or environmentally harmful catalysts and solvents. Specifically, the formation of unwanted by-products should be reduced to avoid laborious purification procedures. The method should be simple and suitable for large-scale production. In addition, the amount of catalyst required should be within the substoichiometric range, and the applied catalyst should be recyclable.

[0022] Surprisingly, it has now been found that these and other objects are achieved by a process which comprises Friedel-Crafts alkylation of the corresponding hydroquinone precursor and then esterification of the condensation product obtained therefrom, both steps being carried out in the presence of a bentonite catalyst.

[0023] Therefore, the present invention relates to a process for preparing a compound of the general formula I,

[0024]

[0025] in

[0026] R 1 , R 2 and R 3 are independently selected from hydrogen and methyl,

[0027] R 4 is selected from C1-C6-alkyl, and

[0028] X is selected from C1-C 20 -alkyl and C2-C 20 -alkenyl,

[0029] The method comprises the following steps:

[0030] a) providing a hydroquinone compound of formula II,

[0031]

[0032] Where R 1 , R 2 and R 3 As defined above,

[0033] b) reacting the hydroquinone compound II provided in step a) with an unsaturated compound of the general formula III.a or III.b in the presence of a bentonite catalyst,

[0034]

[0035] in

[0036] X is defined as above,

[0037] Y is selected from OH, halogen, -OR 11 、-SR 12 and -SO2-R 12 ,

[0038] R 11 is selected from C1-C4-alkyl, C1-C4-alkanoyl and trifluoroacetyl, and

[0039] R 12 is selected from C1-C6-alkyl, trifluoromethyl and phenyl, wherein phenyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 radicals selected from halogen and methyl, and

[0040] c) reacting the condensation product obtained in step b) with a C2-C7-carboxylic acid or with a C2-C7-carboxylic anhydride in the presence of a bentonite catalyst. DETAILED DESCRIPTION

[0041] In the context of the present invention, the term "alkyl" as used herein refers to a group having 1 to 3 ("C1-C3-alkyl"), 1 to 4 ("C1-C4-alkyl"), 1 to 6 ("C1-C6-alkyl"), or 1 to 20 ("C1-C 20 C1-C3-alkyl is methyl, ethyl, propyl and isopropyl. C1-C4-alkyl is furthermore n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C1-C6-alkyl is furthermore, for example, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl or 1,3-dimethylbutyl. C1-C 20 -Alkyl is furthermore, for example, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,4-dimethylpentyl, n-octyl, isooctyl, 2-ethylhexyl, n-nonyl, isononyl, n-decyl, isodecyl, 2-propylheptyl, n-undecyl, isoundecyl, 2,4-dimethylnonyl, n-dodecyl, isododecyl, n-tridecyl, isotridecyl, tetradecyl, isotetradecyl, hexadecyl, isohexadecyl, 4,8,12-trimethyltridecyl, octadecyl, isooctadecyl, etc.

[0042] In the context of the present invention, the term "C1-C4-alkanoyl" denotes a C1-C4-alkyl group as defined above which is linked to the rest of the molecule via a carbonyl [(C=O)] group. The term "C1-C6-alkanoyl" denotes a C1-C6-alkyl group as defined above which is linked to the rest of the molecule via a carbonyl [(C=O)] group. C1-C4-alkanoyl is methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl or 1,1-dimethylethylcarbonyl. C1-C6-Alkanoyl is furthermore, for example, n-pentylcarbonyl, 1-methylbutylcarbonyl, 2-methylbutylcarbonyl, 3-methylbutylcarbonyl, 1,2-dimethylpropylcarbonyl, n-hexylcarbonyl, 1-methylpentylcarbonyl, 2-methylpentylcarbonyl, 3-methylpentylcarbonyl, 4-methylpentylcarbonyl or 1,3-dimethylbutylcarbonyl.

[0043] The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine. Halogen as substituent on the phenyl group is preferably Cl or Br.

[0044] The compound obtainable by the process of the present invention is a compound of general formula (I),

[0045]

[0046] in

[0047] R 1 , R 2 and R 3 are independently selected from hydrogen and methyl,

[0048] R 4 is selected from C1-C6-alkyl, and

[0049] X is selected from C1-C 20 -alkyl and C2-C 20 -alkenyl.

[0050] Due to their structure, the compounds (I) can be present in the form of pure enantiomers or diastereomers and in the form of enantiomeric or diastereomeric mixtures.

[0051] The term "stereoisomer" includes optical isomers, such as enantiomers or diastereomers, the latter being due to the presence of more than one stereocenter in the molecule. Compounds of formula (I) in which X is not methyl have at least one stereocenter, namely a carbon atom in the 2-position of the chromane ring. Furthermore, in compound (I), the group X may also have at least one stereocenter, for example if X is selected from 4,8-dimethylnonyl or 4,8,12-trimethyltridecyl. The present invention relates to the pure enantiomers or diastereomers of compound (I) and mixtures thereof.

[0052] In addition, if the group X is selected as C2-C 20 -alkenyl, compound (I) may also have at least one double bond, which may have E- or Z-configuration, for example, if X represents the isoprenyl moiety 4,8-dimethyl-3,7-nonadienyl or 4,8,12-trimethyl-3,7,11-tridecatrienyl. Therefore, the present invention also relates to compounds (I) in which the double bond (if present) has a pure E- or Z-configuration and / or is present in the form of an E / Z-mixture.

[0053] Preferably, in compounds (I) and (II) of the method of the present invention, the group R 1 , R 2 and R 3 Has the following meanings:

[0054] R 1 Methyl,

[0055] R 2 is a methyl group, and

[0056] R 3 Methyl,

[0057] or

[0058] R 1 Methyl,

[0059] R 2 is hydrogen, and

[0060] R 3 Methyl,

[0061] or

[0062] R 1 For hydrogen,

[0063] R 2 is a methyl group, and

[0064] R 3 Methyl,

[0065] or

[0066] R 1 For hydrogen,

[0067] R 2 is hydrogen, and

[0068] R 3 It is methyl.

[0069] Specifically, in compounds (I) and (II), the group R 1 , R 2 and R 3 It is methyl.

[0070] Preferably, in the compound (I) of the method of the present invention, the group R 4 It is C1-C4-alkyl, more preferably C1-C2-alkyl, in particular ethyl.

[0071] Preferably, in compounds (I), (III.a) and (III.b) of the process of the invention, the moiety X is selected from methyl or has one of the following meanings X-1 to X-6:

[0072]

[0073] Wherein * indicates the point of attachment to the chromane ring.

[0074] Specifically, in compounds (I), (III.a) and (III.b) of the first embodiment, the X moiety is selected from (X-3) or (X-6)

[0075]

[0076] where * indicates the point of attachment to the rest of the molecule.

[0077] In a preferred embodiment, in compound (I)

[0078] R 1 Methyl,

[0079] R 2 is a methyl group, and

[0080] R 3 Methyl,

[0081] or

[0082] R 1 Methyl,

[0083] R 2 is hydrogen, and

[0084] R 3 Methyl,

[0085] or

[0086] R 1 For hydrogen,

[0087] R 2 is a methyl group, and

[0088] R 3 Methyl,

[0089] or

[0090] R 1 For hydrogen,

[0091] R 2 is hydrogen, and

[0092] R 3 Methyl,

[0093] R 4 is C1-C4-alkyl, and

[0094] X is selected from methyl or groups of formulae X-1 to X-6.

[0095] In a more preferred embodiment, in compound (I)

[0096] R 1 Methyl,

[0097] R 2 is a methyl group, and

[0098] R 3 Methyl,

[0099] or

[0100] R 1 Methyl,

[0101] R 2 is hydrogen, and

[0102] R 3 Methyl,

[0103] or

[0104] R 1 For hydrogen,

[0105] R 2 is a methyl group, and

[0106] R 3 Methyl,

[0107] or

[0108] R 1 For hydrogen,

[0109] R 2 is hydrogen, and

[0110] R 3 Methyl,

[0111] R 4 is C1-C2-alkyl, in particular ethyl, and

[0112] X is methyl or has one of the following meanings (X-3) or (X-6):

[0113]

[0114] where * indicates the point of attachment to the rest of the molecule.

[0115] In a specific embodiment, in compound (I)

[0116] R 1 , R 2 and R 3 Methyl,

[0117] R 4 is ethyl, and

[0118] X has one of the following meanings (X-3) or (X-6):

[0119]

[0120] where * indicates the point of attachment to the rest of the molecule.

[0121] Preferably, in compounds (III.a) and (III.b), the group Y is selected from OH, Cl, Br, I, -OR 11 、-SR 12 and -SO2-R 12 ,in

[0122] R 11 is selected from C1-C4-alkanoyl and trifluoroacetyl, and

[0123] R 12 Selected from C1-C3-alkyl, trifluoromethyl, phenyl, 4-methylphenyl and pentafluorophenyl.

[0124] More preferably, in compounds (III.a) and (III.b), the group Y is selected from OH, Br, -OR 11 、-SR 12 and -SO2-R 12 ,in

[0125] R 11 is selected from acetyl and trifluoroacetyl, and

[0126] R 12Selected from methyl, trifluoromethyl and 4-methylphenyl.

[0127] Specifically, in compounds (III.a) and (III.b), the group Y is selected from OH, -OR 11 and -SO2-R 12 ,in

[0128] R 11 is selected from acetyl, and

[0129] R 12 Selected from methyl, trifluoromethyl and 4-methylphenyl.

[0130] Step a):

[0131] Step a) of the present invention comprises providing a hydroquinone compound of the general formula (II).

[0132] These hydroquinone compounds are either commercially available or can be prepared from readily available precursors by methods described in the art.

[0133] Hydroquinone compounds of general formula (II) can be prepared, for example, by reducing the corresponding benzoquinone derivatives of general formula (IV) as shown in Scheme 2.

[0134] Scenario 2:

[0135]

[0136] The reduction step i) is usually carried out by chemical reduction means. Suitable chemical reduction means are, for example, metals in combination with an acid. Metals that react with the acid to form hydrogen are used. Typical metals of this type are zinc, iron, magnesium, aluminum, calcium, manganese, cadmium, etc. The most preferred metals are zinc and iron. Suitable acids are those that have sufficient acidity to react with the metal used. Preferred acids are inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. The most preferred acid is hydrochloric acid. When hydrochloric acid is used in the reduction step, excellent hydroquinone yields can be obtained.

[0137] As an alternative, metal hydrides such as sodium hydride, sodium aluminum hydride, sodium borohydride, etc. may be used.

[0138] Another reduction means that can be advantageously used in the reduction step i) is catalytic hydrogenation. In this variant, the benzoquinone is generally dissolved in an inert solvent and contacted with hydrogen and a hydrogenation catalyst. When carrying out the reduction, any inert solvent can be used, i.e. any solvent that does not react with the starting materials, intermediates and reagents used in the reduction reaction or does not react with the resulting product. Suitable solvents are, for example, alcohols such as methanol, ethanol, propanol and isopropanol; aromatic and substituted aromatic hydrocarbons such as benzene, chlorobenzene, dichlorobenzene, toluene, xylene; and aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, octane, nonane, decane, light petroleum and gasoline ethers; halogenated aliphatic hydrocarbons such as dichloromethane, trichloromethane and tetrachloromethane; ethers such as dibutyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane; and mixtures thereof.

[0139] Suitable hydrogenation catalysts are those that are commonly used in the art for catalyzing the hydrogenation of organic compounds. Some examples of these catalysts include carbon-supported palladium chloride, activated nickel, nickel-nickel oxide, platinum-platinum oxide, carbon-supported platinum, copper chromite, Raney nickel, palladium, platinum black, palladium sponge, nickel, copper-impregnated alumina, palladium black, activated alumina, Raney copper, chromium, vanadium, molybdenum, etc. Particularly suitable hydrogenation catalysts that can be used in the reduction step i) are platinum, palladium, Raney nickel, copper-impregnated alumina and copper chromite.

[0140] The catalytic hydrogenation can be carried out at atmospheric pressure or at elevated pressure. Higher pressures generally result in faster hydrogenation rates. Since benzoquinone is easily reduced, extremely high pressures are not required. Suitable hydrogenation pressures are generally in the range of 1 to 50 bar.

[0141] The hydrogenation is carried out at a temperature high enough to promote the reduction of the benzoquinone, but not so high as to cause degradation of the reactants, reaction medium or products. Suitable reaction temperatures are generally in the range of 20 to 150°C.

[0142] In a preferred embodiment of the present invention, providing the hydroquinone compound II in step a) comprises the following steps:

[0143] a.1) providing a quinone compound of formula IV,

[0144]

[0145] Where R 1 , R 2 and R 3 are independently hydrogen or methyl,

[0146] a.2) catalytically hydrogenating the quinone compound of formula IV provided in step a.1) in the presence of hydrogen and a hydrogenation catalyst.

[0147] The hydrogenation catalysts that can be used in the catalytic hydrogenation in step a.2) are those commonly used in the art for catalyzing the hydrogenation of organic compounds. Some examples of these catalysts include carbon-supported palladium chloride, activated nickel, nickel-nickel oxide, platinum-platinum oxide, platinum black, carbon-supported platinum, copper chromite, Raney nickel, palladium, palladium black, palladium-covered charcoal, sponge palladium, nickel, copper-impregnated alumina, activated alumina, Raney copper, chromium, vanadium, molybdenum, etc.

[0148] Preferably, the hydrogenation catalyst used in step a.2) is a heterogeneous hydrogenation catalyst, more preferably a supported metal catalyst.

[0149] Suitable supports are, for example, carbon, carbon black, activated carbon, graphite, aluminum oxide, silicon oxide, titanium dioxide, zirconium dioxide, cerium dioxide, lanthanum(III) oxide, zinc oxide, silicates, asbestos, silicon carbide, calcium carbonate, magnesium carbonate, magnesium sulfate, barium carbonate, barium sulfate, zeolites, diatomaceous earth and mixtures thereof.

[0150] Even more preferably, the hydrogenation catalyst applied in step a.2) is a carbon-supported catalyst. In particular, the hydrogenation catalyst applied in step a.2) is a carbon-supported noble metal catalyst, ie a noble metal catalyst comprising a support material based on carbon (C), such as activated carbon.

[0151] In principle, suitable carbon-based support materials are all carbon materials known to the person skilled in the art for such purposes. Suitable carbon-based support materials are, for example, carbon, carbon black, activated carbon and graphite. The support material can preferably be used in the form of shaped bodies, granules, wires, pellets, chips, tablets or spheres. The BET surface area (25° C.) of the support material is generally in the range of 1 to 10,000, preferably 10 to 5000 m 2 / g, but is insignificant for the method of the present invention in most cases.

[0152] Suitable noble metals are, for example, selected from Pt, Pd, Ru, Rh and Ir.

[0153] In particular, the hydrogenation catalyst used in step a.2) is selected from carbon-supported Pd catalysts, more particularly from Pd-coated charcoal.

[0154] The metal content of the supported metal catalyst used in step a.2) of the present invention is generally in the range of 0.1 to 20 wt %, preferably in the range of 1 to 15 wt %, based on the total weight of the carbon-supported noble metal catalyst.

[0155] Typically, the amount of hydrogenation catalyst used in step a.2) of the present invention is in the range of 0.05% to 20% by weight, preferably in the range of 0.1% to 10% by weight, more preferably in the range of 0.2% to 5% by weight, based on the amount of quinone present in the reaction mixture.

[0156] The catalytic hydrogenation can be carried out at atmospheric pressure or at elevated pressure. Higher pressures generally lead to faster hydrogenation rates. Since the benzoquinone compound is easily reduced, extremely high pressures are not required. The catalytic hydrogenation in step a.2) is generally carried out at a pressure of 1 to 100 bar, preferably at a pressure of 1 to 50 bar, in particular at a pressure of 2 to 30 bar.

[0157] The hydrogenation is carried out at a temperature high enough to promote the reduction of the benzoquinone compound, but not so high as to cause degradation of the reactants, reaction medium or products. In the preferred embodiment, suitable reaction temperatures are generally in the range of 20 to 150° C., preferably in the range of 30 to 120° C., and especially in the range of 40 to 100° C.

[0158] The quinone compound (IV) provided in step a.1) is commercially available or can be prepared from readily available precursors by methods described in the art.

[0159] For example, as shown in Scheme 3, m-cresol can be catalytically methylated to 2,3,6-trimethylphenol (step ii), and then the 2,3,6-trimethylphenol thus obtained can be oxidized using an oxidizing agent (step iii), thereby preparing 2,3,5-trimethylquinone.

[0160] Scenario 3:

[0161]

[0162] The catalytic methylation in step ii) is usually carried out in the presence of a metal oxide catalyst (e.g., aluminum oxide, silicon oxide, magnesium oxide, calcium oxide, barium oxide, iron oxide, chromium oxide, zinc oxide, manganese oxide, zirconium oxide, thoria, etc.) and a mixed metal oxide catalyst using methanol or dimethyl ether as the alkylating agent.

[0163] The individual reaction conditions for the catalytic methylation of phenols, such as m-cresol, are well known to the skilled person.

[0164] The oxidation in step iii) can be carried out according to standard procedures well known to the skilled person. Typically, the oxidation is carried out in the presence of an oxidizing agent, optionally with the aid of a metal salt or a noble metal catalyst. In principle, all oxidizing agents known to the skilled person that are capable of oxidizing phenols to quinones can be used for the oxidation in step ii).

[0165] Suitable oxidizing agents are, for example:

[0166] - hydrogen peroxide, oxygen or an oxygen-containing gas in the presence of a catalytic amount of a metal salt, for example Mg(II)-, Ca(II)-, Ba(II)-, Cu(II)-, Fe(II), Cr(II)-, Mn(II)-, Co(II)-, Ni(II)-, Zn(II)-sulfates or chlorides and mixtures of these metal salts, or a noble metal catalyst, for example a ruthenium, rhodium, platinum or palladium catalyst;

[0167] - an inorganic acid, for example nitric acid, sulphuric acid, chloric acid, hypochlorous acid, perchloric acid, iodic acid or periodic acid; or

[0168] - Organic peroxyacids, for example perbenzoic acid or meta-chloroperbenzoic acid.

[0169] Suitable reaction conditions for this oxidation reaction are well known to the skilled person.

[0170] In a more preferred embodiment of the present invention, the catalytic hydrogenation reaction in step a.2) is carried out in the presence of a carbonate solvent selected from organic carbonates.

[0171] Preferably, the carbonate solvent is selected from cyclic and linear carbonates of the general formula Va and Vb:

[0172]

[0173] in

[0174] R 15 , R 16 and R 17 are independently selected from hydrogen, methyl and ethyl, in particular from hydrogen and methyl,

[0175] R 18 Selected from hydrogen, phenyl and C1-C 15 -alkyl, where C1-C 15 - alkyl is unsubstituted or substituted by 1, 2 or 3 radicals selected from C1-C3-alkoxy, polyalkylene oxide, phenyl and phenoxy, in particular selected from hydrogen, phenyl, C1-C3-alkyl and benzyl, and

[0176] R 19 are independently selected from C1 -C4 -alkyl, in particular from ethyl and n-propyl.

[0177] More preferably, the carbonate solvent is selected from cyclic and linear carbonates of the general formula Va and Vb:

[0178]

[0179] in

[0180] R 15 , R 16 and R 17 are independently selected from hydrogen and methyl,

[0181] R 18 is selected from hydrogen, methyl, ethyl, phenyl and benzyl, and

[0182] R 19 are independently selected from ethyl and n-propyl.

[0183] Among these carbonate solvents, those having a boiling point of at least 100°C, more preferably at least 120°C, particularly at least 140°C are preferred.

[0184] Specifically, the carbonate solvent is selected from ethylene carbonate, propylene carbonate, butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate, diethyl carbonate and di-n-propyl carbonate.

[0185] These cyclic and acyclic carbonates do not cause any toxicological problems, which is very important for the preparation of compounds of formula I and II. In addition, these solvents have good biodegradability.

[0186] In a more preferred embodiment of the present invention, the catalytic hydrogenation reaction in step a.2) can additionally be carried out in the presence of a non-polar hydrocarbon solvent (HS).

[0187] Therefore, in an alternative embodiment of the present invention, step a.2) is carried out in a solvent mixture consisting of at least one carbonate solvent as defined above and at least one non-polar hydrocarbon solvent (HS).

[0188] Preferably, if present, the non-polar hydrocarbon solvent (HS) is selected from the group consisting of:

[0189] HS.1 Straight-chain and branched alkanes having 5 to 15 carbon atoms, for example pentane, hexane, heptane, octane, nonane, decane, light petroleum and gasoline ether;

[0190] HS.2 Cycloalkanes having 5 to 10 carbon atoms, for example cyclohexane;

[0191] HS.3 Aromatic hydrocarbons having 6 to 12 carbon atoms, for example benzene, toluene, xylene, ethylbenzene and tetralin;

[0192] and mixtures thereof.

[0193] More preferably, the non-polar hydrocarbon solvent (HS) is selected from the group HS.1 and HS.2.

[0194] Specifically, the non-polar hydrocarbon solvent (HS) is selected from hexane, cyclohexane, heptane, octane and nonane, more specifically selected from heptane and octane.

[0195] In this alternative embodiment, the content of carbonate solvent in the solvent mixture is generally in the range of 35 to 99 wt %, preferably in the range of 50 to 99 wt %, and particularly in the range of 50 to 90 wt %, based on the total weight of the solvent mixture.

[0196] Therefore, the weight ratio of the carbonate solvent to HS used in step a.2) is generally in the range of 1:3 to 100:1, preferably in the range of 1:1 to 100:1, in particular in the range of 1:1 to 10:1.

[0197] In this alternative embodiment, carbonate solvents are preferred, which are immiscible or only slightly miscible with at least one non-polar hydrocarbon solvent (HS), which means that step a.2) is carried out in a two-phase solvent mixture consisting of a carbonate solvent phase and a HS phase. In this context, the term "slightly miscible" means that less than 5% by weight, preferably less than 2% by weight, more preferably less than 1% by weight, in particular less than 0.5% by weight of polar aprotic solvent (PS) is present in the HS phase.

[0198] In this alternative embodiment, preference is given to solvent mixtures consisting of at least one carbonate solvent and at least one nonpolar hydrocarbon solvent of group HS.1.

[0199] Specifically, in this alternative embodiment, the solvent mixture consists of at least one carbonate solvent selected from the group consisting of ethylene carbonate, propylene carbonate, butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate, diethyl carbonate and di-n-propyl carbonate and at least one non-polar hydrocarbon solvent (HS) selected from the group consisting of heptane and octane.

[0200] In a particular embodiment of the present invention, step a.2) is carried out in at least one carbonate solvent (PS) as defined above.

[0201] The catalytic hydrogenation can be carried out in various reactors known for this purpose, for example a series of loop reactors as described in US 5,756,856, but also in simpler reactors as described, for example, in DE 2008128. Preference is given to fixed bed reactors, in particular trickle bed reactors.

[0202] The reaction product obtained in step a.2), ie the compound of formula (II), is usually worked up by filtering off the hydrogenation catalyst. The reaction mixture thus obtained can be used directly in step b) of the process.

[0203] If desired, the reaction mixture thus obtained can be worked up further in a customary manner, for example by mixing with water, separating the phases and, where appropriate, purifying the crude product by using chromatography, by distillation or by recrystallization.

[0204] In a preferred embodiment of the present invention, the reaction mixture obtained in step a.2) is used directly in the reaction in step b) of the process after removal of the hydrogenation catalyst.

[0205] Step b):

[0206] Step b) of the present invention comprises reacting the compound (II) provided in step a) with an unsaturated compound of the general formula (III.a) or (III.b) in the presence of a bentonite catalyst,

[0207]

[0208] in

[0209] X has one of the meanings given above,

[0210] Y is selected from OH, halogen, -OR 11 、-SR 12 and -SO2-R 12 ,

[0211] R 11 is selected from C1-C4-alkyl, C1-C4-alkanoyl and trifluoroacetyl, and

[0212] R 12 is selected from C1-C6-alkyl, trifluoromethyl and phenyl, wherein phenyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from halogen and methyl.

[0213] Bentonite is formed from highly colloidal and plastic clay. Bentonite is commonly used as a thickener and filler for paints, ceramics and additives for health products (such as cosmetics / nutraceuticals or pharmaceuticals). Bentonite is a good adsorbent and is characterized by high cation exchange capacity, strong swelling capacity and low permeability.

[0214] As used herein, the term "bentonite" or "bentonite catalyst" may generally include all types of silicate clay minerals containing the elements H, C, O, Si, Al, Mg, Ca, Li, Na, K, Fe, Zn, S, F, and all combinations thereof. For example, "bentonite" or "bentonite catalyst" may include pyrophyllite, talc, micas (e.g., muscovite, paragonite, phlogopite, biotite, lepidolite, ferrolithite, taenia, fluoro-tetrasilicon mica), brittle micas (pearlite, chlorite, seyberite, green brittle micas), hydrous micas, illite, chlorite, vermiculite, montmorillonite (montmorillonite, saponite, nontronite, beidellite, sauconite, hectorite, fluorohectorite), kaolinite, serpentine, and / or palygorskite (attapulgite, sepiolite). Preferably, "bentonite" or "bentonite catalyst" includes montmorillonite as described, for example, in Klockmann's textbook of mineralology, 16th edition, F. Euke Verlag 1978, pages 739-765; and RM Barrer Zeolites and Clay Minerals as Sorbents and Molecular Sieves, Academic Press, and Y. Izumi, K. Urabe, M. Onaka Zeolite, Clay, and Heteropoly Acid in Organic Reactions, VCH.

[0215] Typically, the main component of bentonite is montmorillonite, a clay mineral of the smectite family. Montmorillonite consists of two layers of silicon tetrahedrons with an intermediate layer of aluminum octahedrons in between. It has hydroxyl groups between the layers and on the surface.

[0216] In principle, all montmorillonite-containing deposits, such as those listed in the special paper "The Economics of Bentonite" (The Economics of Bentonite) of Roskill Information Services Ltd, London, 8th edition, 1997, can be considered as suitable bentonite sources. Depending on its source, bentonite can also contain various associated minerals and non-mineral components mentioned above in different amounts in addition to montmorillonite. Such associated minerals and non-mineral components are in particular quartz, feldspar, kaolin, muscovite, zeolite, titanium oxide, iron oxide, illite, mica, calcite and / or gypsum. Preferred raw materials are those with high montmorillonite content and correspondingly low second component content, because the amount of pure montmorillonite in bentonite determines its performance. The higher the content of montmorillonite in bentonite, the better its performance as an industrial raw material. The montmorillonite content can be measured, for example, by adsorption of methylene blue.

[0217] Preferred raw materials have a methylene blue value of at least 250 mg / g, preferably at least 290 mg / g, and in particular at least 320 mg / g. Particularly preferred raw materials are raw materials whose exchangeable cations are composed of a high percentage of alkali metals, in particular sodium. In terms of charge equivalent, these raw materials contain at least 25%, preferably at least 40% of monovalent exchangeable cations. These sodium bentonite raw materials exist in nature, and known sources of sodium-containing bentonites are, for example, in Wyoming, USA / USA or in India, where they are also called "Western bentonites" because of their origin, "Wyoming bentonites" or "swelling bentonites" because of their properties. Bentonites with a higher proportion of alkaline earth metal cations (especially calcium) are called "subbentonites" or "southern bentonites" and can be converted into sodium-containing bentonites by alkali activation.

[0218] Finally, in principle, suitable synthetic clay minerals can also be prepared, for example by columnization with organic or metal complex cations (PILC) and used in the present invention (MM Herling et al. Z. Anorg. Allg. Chem. 2014, 640, 3-4. 547-560; G. Poncelet and JJ Fripiat Handbook of Heterogeneous Catalysis (2 nd Edition)2008,1,219-247).

[0219] Besides mineral impurities, clay minerals of natural origin may also contain non-mineral impurities, in particular carbon compounds.Preferred starting materials are bentonites having a total carbon content of less than 3% by weight, preferably less than 1% by weight, particularly preferably less than 0.5% by weight.

[0220] It is well known that the macroscopic properties and applicability of bentonite are closely related to the quantity and quality of montmorillonite contained therein, its pH value (residual acidity), particle size and its porous microstructure (e.g. surface area, porosity).

[0221] Bentonite can be divided into natural bentonite (ie, untreated bentonite) and treated bentonite (see, for example, Nones et al., Applied Clay Science, 2015, 105-106, 225-230). In a preferred embodiment of the present invention, the reaction in step b) is carried out in the presence of a treated bentonite catalyst.

[0222] As used herein, the term "treated bentonite" refers to bentonite in which the structure, texture and other properties of the bentonite are modified by chemical treatment and / or heat treatment. Therefore, the term "treated" used herein refers to chemical treatment and / or heat treatment, and the term "treated bentonite" refers to chemically treated and / or heat-treated bentonite. Generally, the chemical treatment of bentonite includes acid treatment, alkali treatment, metal salt treatment (cation exchange) or organic treatment. Bentonite obtained by acid treatment or alkali treatment is also referred to as "activated bentonite" (acid-activated bentonite or alkali-activated bentonite).

[0223] Preferably, the chemical treatment of the bentonite catalyst comprises a metal salt treatment (cation exchange) or an acid treatment.

[0224] In a more preferred embodiment of the present invention, the reaction in step b) is carried out in the presence of an acid-treated bentonite catalyst.

[0225] As used herein, the term "acid-treated bentonite" or "acid-activated bentonite" refers to bentonite treated with a Bronsted acid, for example an inorganic acid such as HCl or H2SO4, H3PO3, HNO3, boric acid, silicic acid, carboxylic acids (e.g., formic acid or acetic acid), or other organic acids such as trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid or trifluoromethanesulfonic acid. HCl and / or H2SO4, or a mixture of HCl and / or H2SO4 with other inorganic or organic acids is preferred. Typically, acid-activated bentonite is used on a large scale as a bleaching earth for oil discoloration.

[0226] It is also known that treatment with inorganic acids imparts surface acidity to clays, which improves their catalytic properties (P. Komandel, Applied Clay Science, 2016, 131, 84-99; DAD'Amico et al. Applied Clay Science, 2014, 99, 254-260). Without being bound by theory, it is believed that during the acid treatment or acid activation, respectively, the edges of the silicate sheets of the clay minerals in the bentonite open and the Al2O3 of the octahedral sheets are activated. 3+ and Mg 2+ The cations become soluble. The chemistry of this activation process is shown, for example, in J. Amorimet al. Hydrocarbon Engineering 2016, 21, 11, 83-8, where acidic hydrogen ions, such as those from sulfuric acid, open the sheet structure of clay minerals in bentonite and form acid sites. The final acid-treated bentonite contains amorphous, porous, protonated and hydrated silica with a three-dimensional cross-linked structure (P. Komandel Applied Clay Science, 2016, 131, 84-99).

[0227] The preparation of acid-activated clay minerals, in particular layered silicates, such as bentonites, is well known in the art; for example EP 0 398 636 (B1) provides an overview and detailed methods for the acid activation of clay minerals such as bentonites can be found, for example, in DE 10 2 45 198 (A1).

[0228] Alkali treatment of bentonite involves treating the bentonite with an inorganic base such as NaOH, KOH or sodium carbonate, or an organic base such as ammonia, trimethylamine or tetraalkylammonium hydroxide. Alkali activation is usually performed by treatment with sodium carbonate.

[0229] Organic treatment of bentonite involves treating the bentonite with an organic compound such as a quaternary ammonium cation (eg, alkylammonium and α-ω-dialkylammonium).

[0230] Other organic and inorganic compounds that can be exchanged into the above-mentioned minerals include: hydrazine, urea, formamide, acetamide, Li, Na, K, Rb, Cs and NH4 salts of lower fatty acids (acetates, propionates, cyanoacetates), oxalates, glycolates, alanine esters, lysine salts, lactates, glycerol, acetylacetone, α-methoxyacetylacetone, ethyl acetoacetate, nonanetrione-2:5:8, hexanedione-2:5, β:β'-oxydipropionitrile, β-ethoxypropionitrile, tetracyanoethylene, 7,7,8,8-tetracyanoquinomethane, bis-(2-ethoxyethyl)-ether, bis-(2-methoxyethyl)-ether, ethylene glycol diglycidyl ether, triethylene glycol, diethylene glycol, triethylene glycol diacetate, diethylene glycol diacetate, hexanediol-1:6, pentanediol-1:5, 2:4-hexadiynediol-1:6.

[0231] Other organic bases that exchange into the above-mentioned minerals are amines, such as n-propylamine, n-butylamine, n-hexylamine, n-octylamine, benzidine, N,N,N',N'-tetramethylbenzidine, diethylamine, triethylamine, triphenylamine, p-phenylenediamine, N,N'-dimethyl-p-phenylenediamine, N,N,N',N'-tetramethyl-p-phenylenediamine, trans-4,4'-diaminostilbene dihydrochloride, benzylamine, aniline, and o-toluidine.

[0232] Other long chain alkylammonium salts exchanged into the above minerals are 1-n-alkylpyridinium bromide and cetyltrimethylammonium bromide.

[0233] In addition, glycine and its peptides are described in RM Barrer Zeolites and Clay Minerals as Sorbents and Molecular Sieves, Academic Press, and references cited therein, in exchange for various other amino acids and ligands entering the above-mentioned minerals.

[0234] Preferably, the "acid-treated bentonite catalyst" is selected from bentonite treated with an inorganic acid and bentonite treated with a strong organic acid. In particular, the "treated bentonite catalyst" is selected from bentonite treated with an inorganic acid.

[0235] These bentonite catalysts do not cause corrosion problems for reaction equipment or contamination of wastewater with metal ions or inorganic acids, and have sufficient acidity to carry out the reaction of step b) at a reasonable to high reaction rate.

[0236] Acid-treated bentonites are commercially available, or they can be prepared using methods well described in the art, as described above.

[0237] Commercially available acid-treated bentonites (e.g. also known as acid-leached bentonites with CAS number 70131-50-9) which can be used as catalysts in the reaction of step b) are, for example:

[0238] - montmorillonite K10, montmorillonite K 30, montmorillonite (aluminum pillared clay) (CAS 139264-88-3), montmorillonite-KSF (CAS 1318-93-0), available from, for example, Sigma-Aldrich;

[0239] -TONSIL from Clariant Produkte (Deutschland) GmbH TM catalyst.

[0240] Typically, the bentonite catalyst used in step b) of the process has a catalyst content of between 50 and 800 m 2 / g, preferably in the range of 100 to 600 m 2 / g, more preferably in the range of 120 to 500 m 2 / g range, especially in the range of 150 to 400 m 2 / g. As used herein, the expression "BET surface area" refers to the well-known Brunauer-Emmett-Teller method for determining surface area. The BET surface area values ​​given in this application are determined by the BET method via nitrogen adsorption, largely following DIN 66131 (1973), as described in detail below.

[0241] Typically, the bentonite catalyst used in step b) of the present process has a residual acidity determined by potentiometric titration expressed in mg KOH / g bentonite in the range of 3 to 70, preferably in the range of 5 to 50, more preferably in the range of 10 to 45, in particular in the range of 15 to 40. The residual acidity (mg KOH / g bentonite) is determined by following a standard procedure, as described in the following experimental part.

[0242] In short, the determination of the residual acidity of the bentonite catalyst is carried out in the following manner: first, an aqueous suspension with a certain amount of solid catalyst is prepared. Then, an aqueous NaOH solution with a defined concentration is titrated into the aqueous suspension until the pH value of the bentonite suspension switches to the alkaline range (pH>7.0), which represents the endpoint of the titration. The pH value is determined by a potentiometer using a pre-calibrated KCl-pH electrode (potential indication). Then, the amount of NaOH required to reach the titration endpoint (in milligrams) / gram of bentonite catalyst used in the aqueous suspension is calculated. The calculated value corresponds to the residual acidity in mgKOH / g bentonite.

[0243] Typically, the amount of free moisture in the treated bentonite catalyst is at most 30 wt%, preferably at most 25 wt%, more preferably at most 20 wt%.

[0244] The content of free moisture in the treated bentonite is determined by weighing the individual bentonites relative to an anhydrous sample of the same bentonite, the anhydrous sample being obtained by drying in a vacuum oven at a temperature range of 100 to 200° C., optionally at a reduced pressure of less than 200 mbar, preferably at a temperature range of 100 to 150° C. and at a reduced pressure of less than 10 mbar, in particular less than 1 mbar, until constant weight.

[0245] In this more preferred embodiment, the amount of bentonite catalyst used in step b) of the process of the invention is in the range of 1 to 750 g per mole of the unsaturated alkanol of the general formula III.a or III.b used in step b). Preferably, the amount of bentonite catalyst used in step b) is in the range of 5 to 500 g per mole of compound III.a or III.b, more preferably in the range of 10 to 250 g per mole of compound III.a or III.b, even more preferably in the range of 15 to 200 g per mole of compound III.a or III.b, in particular in the range of 20 to 150 g per mole of compound III.a or III.b used in step b).

[0246] Typically, the weight ratio of the treated bentonite catalyst to compound (II) used in step b) is 0.01:1 to 2.5:1, preferably 0.03:1 to 1.3:1, more preferably 0.04:1 to 1:1, especially 0.05:1 to 0.7:1.

[0247] The porous structure of bentonite can be further modified by hydration and dehydration processes, such as thermal activation (LA Shah et al. Applied Clay Science, 2018, 162, 155-164).

[0248] In a particularly preferred embodiment of the present invention, the treated bentonite catalyst is subjected to a drying step before being used in step b).

[0249] The drying step is generally carried out at a temperature in the range of 50 to 200°C, preferably in the range of 70 to 170°C, in particular in the range of 80 to 150°C, especially in the range of 100 to 120°C.

[0250] The drying step can generally be carried out at ambient pressure or at reduced pressure. Preferably, the drying step is preferably carried out at reduced pressure. Specifically, the drying step is carried out at a pressure of 0.1 to 500 mbar, more specifically 1 to 200 mbar.

[0251] The drying time of the bentonite catalyst depends on the temperature and pressure applied in the drying step and can therefore vary within a wide range. Typically, the drying time of the treated bentonite catalyst is in the range of a few minutes to a few days, but preferably in the range of 30 minutes to 2 days.

[0252] The reaction in step b) is generally carried out at a temperature of 50 to 200°C, preferably 70 to 170°C, in particular 80 to 150°C.

[0253] The reaction in step b) can generally be carried out under ambient pressure or under elevated or reduced pressure.

[0254] The reaction in step b) can be carried out in the absence or presence of an inert gas. As used herein, the expression "inert gas" generally refers to a gas that does not react with the starting materials, reagents or solvents involved in the reaction or with the resulting product under the prevailing reaction conditions. Preferably, the reaction in step b) is carried out in the presence of an inert gas, preferably in the presence of argon or nitrogen, in particular in the presence of nitrogen.

[0255] The reaction in step b) is usually carried out in the presence of an organic solvent. Preferably, the solvent used in step b) of the present invention is selected from at least one polar aprotic solvent (PS) and a solvent mixture consisting of at least one polar aprotic solvent (PS) as defined above and at least one non-polar hydrocarbon solvent (HS).

[0256] Suitable polar aprotic solvents (PS) are, for example, selected from the following group (the values ​​in brackets refer to the respective boiling points of the solvents mentioned by way of example):

[0257] PS.1 Organic carbonates, i.e. linear and cyclic carbonates, for example ethylene carbonate (243°C), propylene carbonate, butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate, dimethyl carbonate (90°C), diethyl carbonate (128°C) and di-n-propyl carbonate;

[0258] PS.2 Ketones, such as diethyl ketone (102°C) or methyl isobutyl ketone (116°C);

[0259] PS.3 Lactone, such as γ-butyrolactone (204-206°C);

[0260] PS.4 Lactam, such as N-methyl-2-pyrrolidone (NMP, 203°C);

[0261] PS.5 Nitriles, such as acetonitrile (82°C) and valeronitrile (117°C);

[0262] PS.6 Nitro compounds, such as nitromethane (101°C);

[0263] PS.7 Tertiary carboxamides, such as dimethylformamide (153°C);

[0264] PS.8 Urea derivatives, such as tetramethylurea (177°C) and dimethylpropyleneurea (DMPU, 247°C);

[0265] PS.9 sulfoxide, such as dimethyl sulfoxide (DMSO, 189°C);

[0266] PS.10 Sulfone, such as sulfolane (285℃)

[0267] PS.11 alicyclic ethers, such as 1,4-dioxane (101°C);

[0268] PS.12 Glycol ethers, for example alkylene glycol dialkyl ethers, dialkylene glycol dialkyl ethers and polyalkylene glycol dialkyl ethers;

[0269] and mixtures thereof.

[0270] Within this group, preference is given to those polar aprotic solvents (PS) having a boiling point of at least 100°C, more preferably at least 120°C, in particular at least 140°C.

[0271] More preferably, the polar aprotic solvent (PS) is selected from the group PS.1, PS.3, PS.4, PS.7, PS.8, PS.9, PS.10 and PS.12, even more preferably PS.1, PS.7, PS.8 and PS.12, even more preferably from PS.1 and PS.12, in particular from PS.1.

[0272] In particular, the polar aprotic solvent (PS) is selected from cyclic and linear carbonates of the general formula Va and Vb as defined above.

[0273] Preferably, the non-polar hydrocarbon solvent (HS) is selected from the groups HS.1 and HS.2.

[0274] More preferably, the non-polar hydrocarbon solvent (HS) is selected from hexane, cyclohexane, heptane, octane and nonane, more particularly from heptane and octane.

[0275] In a preferred embodiment of the present invention, step b) is carried out in a solvent mixture consisting of at least one polar aprotic solvent (PS) as defined above and at least one nonpolar hydrocarbon solvent (HS) as defined above.

[0276] In this preferred embodiment, the content of PS in the solvent mixture is generally in the range of 35 to 99 wt %, preferably in the range of 50 to 99 wt %, in particular in the range of 50 to 90 wt %, based on the total weight of the solvent mixture.

[0277] Therefore, the weight ratio of PS to HS used in step b) is generally in the range of 1:3 to 100:1, preferably in the range of 1:1 to 100:1, in particular in the range of 1:1 to 10:1.

[0278] In this preferred embodiment, preference is given to polar aprotic solvents (PS) which are immiscible or only slightly miscible with the at least one nonpolar hydrocarbon solvent (HS), which means that step b) is carried out in a two-phase solvent mixture consisting of a PS phase and a HS phase. In this context, the term "slightly miscible" means that less than 5% by weight, preferably less than 2% by weight, more preferably less than 1% by weight and in particular less than 0.5% by weight of polar aprotic solvent (PS) is present in the HS phase.

[0279] In this preferred embodiment, preference is given to solvent mixtures consisting of at least one polar aprotic solvent of group PS.1 and at least one nonpolar hydrocarbon solvent of group HS.1.

[0280] In particular, in this preferred embodiment, the solvent mixture consists of at least one polar aprotic solvent (PS) selected from ethylene carbonate, propylene carbonate, butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate, diethyl carbonate and di-n-propyl carbonate and at least one non-polar hydrocarbon solvent (HS) selected from heptane and octane.

[0281] In a particular embodiment of the present invention, step b) is carried out in at least one polar aprotic solvent (PS) as defined above.

[0282] The compound of formula (II) used in step b) is highly soluble in polar aprotic solvents (PS phase), while the non-polar reaction product obtained in step b), i.e., the alkylation or condensation product (which is usually separated from the polar aprotic solvent after the reaction mixture is cooled) is highly soluble in non-polar hydrocarbon solvents (HS phase). Therefore, the advantage of using the above solvent mixture is that the reaction mixture obtained in step b) can be easily separated into a PS phase (containing most or substantially all of the unreacted compound (II) and the condensation catalyst) and a HS phase (containing most or substantially all of the non-polar reaction product obtained in step b) by phase separation. If necessary, the non-polar reaction product obtained in step b) can be separated from the PS phase by extraction with a non-polar hydrocarbon solvent (HS). The separated PS phase can then be returned to the reaction in step b) or used later in another reaction in step b). The separated HS phase can be directly subjected to the next process step or purification step. Furthermore, the water formed during the reaction of step b) can be easily distilled off from the PS phase, thereby allowing easy recycling of the polar aprotic solvent (PS). In addition, the use of a non-polar hydrocarbon solvent (HS) allows efficient distillation removal of the water formed during the reaction of step b) by forming an azeotropic mixture.

[0283] The concentration of compound (II) in the polar organic solvent (PS) is generally in the range from 2 to 50% by weight, preferably in the range from 3 to 45% by weight, in particular in the range from 5 to 40% by weight.

[0284] The molar ratio of compound (II) to compound III.a or III.b used in step b) is generally in the range of 1:1 to 10:1, preferably in the range of 1.05:1 to 5:1, more preferably in the range of 1.05:1 to 3:1, in particular in the range of 1.1:1 to 2:1.

[0285] Compounds of the general formula III.a and III.b are either commercially available or can be prepared from readily available precursors by methods described in the art or can be obtained from natural sources.

[0286] For example, compounds III.a and III.b in which Y is a hydroxyl group are readily commercially available or can be obtained from natural sources. Compounds III.a and III.b as defined above, in which Y represents a leaving group different from a hydroxyl group, can be prepared from the corresponding alcohol precursors by conventional nucleophilic substitution reactions. These nucleophilic reactions can be carried out under conventional reaction conditions well known to the skilled person.

[0287] Typically, the reaction in step b) of the process of the invention is first carried out with the formation of a Friedel-Crafts alkylation product. In the case where the hydroxyl group adjacent to the alkylation position is not protected, the Friedel-Crafts alkylation reaction is usually followed by a subsequent ring closure reaction (intramolecular hydroxyalkylation of the double bond) to form a fused six-membered ring containing an oxygen atom. If desired, the intermediate Friedel-Crafts alkylation product can also be isolated and the ring closure reaction can be carried out in a separate step. However, it is preferred to carry out the Friedel-Crafts alkylation and the ring closure reaction in a single step.

[0288] In a preferred embodiment of the present invention, the reaction in step b) is carried out by distilling off at least a portion of the water formed during the reaction. As described above, in addition to the polar aprotic solvent (PS) in the step, the distillation of the water formed during the reaction can also be promoted by using a non-polar hydrocarbon solvent (HS), such as cyclohexane, heptane, octane or toluene, because the non-polar hydrocarbon solvent (HS) usually forms an azeotropic mixture with water. For this reason, the steam is removed from the reaction system and condensed. If the steam consists of an azeotropic mixture of water and the organic solvent used in step b) and / or another component of the reaction mixture of step b), or the water contains a large amount of product or starting material, the resulting condensate is usually subjected to phase separation to obtain an aqueous phase and an organic phase. For this reason, the condensate usually enters a phase separator (decanter), where mechanical sedimentation decomposes it into two phases that can be extracted separately. If necessary, before the condensate enters the phase separator, a water-immiscible organic solvent, preferably an organic solvent used in step b), is added to the condensate. Remove and discard the aqueous phase, and return the organic phase to the reaction system at least to some extent. “Returning to the reaction system” means passing the organic phase into any desired at least one reactor in the reaction system.

[0289] Any suitable condenser can be used for the condensation or partial condensation of the steam. These can be cooled by any desired coolant. Preferably, the condenser has air cooling and / or water cooling, particularly preferably air cooling.

[0290] As mentioned above, the reaction in step b) can be carried out in a batch mode (discontinuous mode), or in a continuous mode. Preferably, the reaction in step b) is carried out in a continuous mode.

[0291] If the reaction in step b) is carried out in a batchwise (discontinuous) manner, the reactants and catalyst are generally placed in a suitable reaction vessel, such as a stirred vessel or a loop reactor, at the temperature indicated above until the desired conversion is reached. Depending on the amount of catalyst added, the reaction time may be from 0.5 to 30 hours, preferably from 1 to 20 hours.

[0292] Preferably, the reaction in step b) is carried out in the following manner: first, an organic solvent and a bentonite catalyst, preferably an acidic heterogeneous catalyst, in particular a treated bentonite catalyst, are placed in a suitable reaction vessel, such as a stirred vessel or a loop reactor, and then heated to the reaction temperature. Optionally, the resulting suspension is kept at the reaction temperature for a few minutes, such as 1, 2, 5, 10, 15 or 20 minutes, before the suspension is cooled to below 80°C. In these pretreatment steps, an inert gas, preferably argon or nitrogen, is introduced into the apparatus to ensure that the apparatus is free of oxygen. Then, compound (II) is added once to the preheated solvent / catalyst suspension, and the resulting mixture is heated to the reaction temperature. Thereafter, compound III.a or III.b is added to the reaction mixture, optionally dissolved in a non-polar hydrocarbon solvent (HS). Typically, compound III.a or III.b is added gradually to the reaction mixture (comprising organic solvent, condensation catalyst and compound (II)) in several portions (e.g., in 2, 3, 4, 5, 10, 15 or 20 portions), or is metered in continuously. Preferably, compound III.a or III.b is metered in continuously. The addition rate of compound III.a or III.b to the reaction mixture is typically in the range of 0.2 to 5% by volume / minute, preferably in the range of 0.3 to 3% by volume / minute, and in particular in the range of 0.5 to 2% by volume / minute, based on the total volume of compound III.a or III.b.

[0293] Depending on whether a polar aprotic solvent (PS) alone or a mixture of a polar aprotic solvent (PS) and a non-polar hydrocarbon solvent (HS) is used as the organic solvent in step b), the desired reaction product is separated from the resulting reaction mixture by phase separation and / or by extraction with a non-polar hydrocarbon solvent (HS). In this way, two phases are obtained, namely a PS phase which predominantly comprises the condensation catalyst and ultimately unreacted compound (II), and a HS phase which predominantly comprises the desired reaction product and ultimately unreacted compound III.a or III.b. After phase separation and / or extraction, the reaction product can be purified by chromatography, distillation and / or crystallization, preferably by distillation, or the reaction product can be directly subjected to the next reaction step b).

[0294] In a preferred embodiment of the present invention, the bentonite catalyst used in step b) of the process, in particular the treated bentonite catalyst, is separated from the reaction mixture or the PS phase after completion of the reaction and reused in the further reaction in step b).

[0295] In order to separate bentonite catalyst, particularly treated bentonite catalyst from reaction mixture or PS phase, all methods suitable for separating solid from liquid mixture known to those skilled in the art can generally be used. Preferably, bentonite catalyst is removed from the obtained reaction mixture by filtration. After separation, bentonite catalyst, particularly treated bentonite catalyst, is dried in an inert gas stream, preferably in a nitrogen stream. Depending on the properties of the solvent used in the reaction in step b), the drying time of bentonite catalyst, particularly treated bentonite catalyst in an inert gas stream can vary over a wide range. The drying time of bentonite catalyst in an inert gas stream is generally in the range of a few minutes to a few days, i.e. 5 minutes to 5 days. The drying time of bentonite catalyst in an inert gas stream can be, for example, 10 minutes, 30 minutes, 1 hour, 5 hours, 12 hours, 1 day, 3 days or 5 days.

[0296] In another preferred embodiment of the present invention, the PS phase comprising predominantly bentonite catalyst and ultimately unreacted compound (II), obtained after phase separation and / or extraction of the reaction mixture obtained in step b) with a non-polar hydrocarbon solvent, is directly reused in the further reaction in step b).

[0297] The reaction in step b) can be carried out batchwise or continuously. Preferably, the reaction in step b) is carried out continuously.

[0298] The continuous reaction is usually carried out in at least one reactor, for example 1, 2, 3, 4 or 5 reactors, preferably in one reactor, the reactor comprising a fixed bed or moving bed form, preferably a treated bentonite catalyst in the form of a fixed bed, for example, a mixture of an organic solvent and compound III and compound III.a or III.b is fed into the reactor. In a preferred fixed bed operation mode, the reactor can be operated in a sump operation mode, that is, the reaction mixture is guided from the bottom to the top, or in a trickle operation mode, that is, the reaction mixture is guided from the top to the bottom through the reactor. As described above, the water formed during the reaction can be removed by discharging steam from the top of the reactor, and the steam is condensed and separated into an organic phase (finally containing a non-polar hydrocarbon solvent (HS) and a small amount of unreacted compound II and / or reaction products) and an aqueous phase. The organic phase is optionally returned to at least one reactor. A reaction mixture stream containing a polar aprotic solvent (PS), a non-polar hydrocarbon solvent (HS) (if present), a reaction product and finally unreacted compound III is discharged from the bottom of the reactor. Depending on whether a polar aprotic solvent (PS) alone or a mixture of a polar aprotic solvent (PS) and a nonpolar hydrocarbon solvent (HS) is used as the organic solvent in step b), the desired reaction product is separated from the resulting reaction mixture by phase separation and / or by extraction with a nonpolar hydrocarbon solvent (HS). The reaction product can then be purified or can be directly subjected to the next reaction step.

[0299] The catalyst hourly space velocity for the reaction in step b) is preferably in the range from 0.1 to 50 kg of compound III.a or III.b per kg of catalyst and hour, in particular in the range from 0.2 to 30 kg of compound III.a or III.b per kg of catalyst and hour.

[0300] The at least one reactor may be selected from any desired reactor suitable for carrying out heterogeneously catalyzed chemical reactions in the liquid phase.

[0301] Suitable reactors are non-backmixing reactors, such as tubular reactors or residence time vessels provided with internals, but preferably backmixing reactors, such as stirred tank reactors or loop reactors. However, it is also possible to use a combination of continuous backmixing reactors and non-backmixing reactors.

[0302] Optionally, several reactors can also be combined in a multistage apparatus. Such reactors are, for example, loop reactors with combined sieve trays, cascade vessels, tubular reactors with temporary feed points or stirred columns.

[0303] Step c):

[0304] In step c) of the process according to the invention, the condensation product obtained in step b) is reacted with a C2-C7-carboxylic acid or with a C2-C7-carboxylic anhydride in the presence of a bentonite catalyst.

[0305] According to the present invention, the reaction in step c) is carried out in the presence of a bentonite catalyst.

[0306] Suitable and preferred bentonite catalysts which may be used in step c) of the process of the present invention are as defined above.

[0307] In a preferred embodiment of the present invention, step c) is carried out in the presence of the same bentonite catalyst as applied in step b).

[0308] Preferably, in this preferred embodiment, the bentonite catalyst used in steps b) and c) is separated from the reaction mixture after completion of the reaction in step c) and reused in the further reaction in step b). The recycling of the bentonite catalyst is carried out as described above for step b).

[0309] In a more preferred embodiment of the present invention, the esterification reaction in step c) is carried out in the presence of a treated bentonite catalyst, in particular in the presence of an acid-treated bentonite catalyst as described above.

[0310] In a particularly preferred embodiment of the present invention, steps b) and c) are carried out in the presence of a carbonate solvent as defined above.

[0311] In another particular embodiment of the present invention, the reactions in steps b) and c) are carried out in the presence of a carbonate solvent / non-polar hydrocarbon solvent mixture as described above.

[0312] Suitable and preferred carbonate solvents and suitable and preferred non-polar hydrocarbon solvents (HS), if present, are as defined above.

[0313] Even more preferably, in this particular embodiment, step c) is carried out in the same carbonate solvent as applied in step b) and, if present, in the same non-polar hydrocarbon solvent (HS).

[0314] In particular, the reaction mixture obtained in step b) is directly used in the reaction in step c), ie, step b) and step c) are carried out as a one-pot reaction.

[0315] The reaction product obtained in step c), i.e. the compound of formula (I), can be worked up in a conventional manner, for example, by filtering off any solid catalyst (if present); by adding a non-polar hydrocarbon solvent (HS) if necessary; by separating the phases; and, where appropriate, by using chromatography, by distillation (if applicable) or by recrystallization to purify the crude product.

[0316] In a specific embodiment of the present invention, steps a.2), b) and c) are carried out in the same carbonate solvent and, if present, in the same non-polar hydrocarbon solvent (HS). Preferably, in this specific embodiment, after removing the hydrogenation catalyst, the reaction mixture obtained in step a.2) is directly used in the reaction in step b), and the reaction mixture obtained in the subsequent step b) is directly used in the reaction in step c).

[0317] The process of the present invention provides compound (I) in high yield and selectivity. Typically, compound (I) is further purified by recrystallization, distillation (if applicable) or by using a chromatographic method.

[0318] Typically, only small amounts of by-products are obtained.

[0319] Frequent by-products obtained by using the processes described in the prior art for preparing compounds of the general formula (I) are, for example, diene compounds of the general formulae X.1 to X.3, which are formed from III.a or III.b by undesired elimination reactions, as shown in Scheme 4.

[0320] Solution 4:

[0321]

[0322] in

[0323] X is as defined above, and

[0324] X-2 is preferably selected from the moieties of formula X-2.a and X-2.b:

[0325]

[0326] in

[0327] n is an integer from 0 to 2, and

[0328] *Indicates the point of attachment to the rest of the molecule.

[0329] The formation of these diene by-products is generally increased when carboxylic acids such as oxalic acid, tartaric acid or citric acid are used as condensation catalysts. These acids are able to form ester intermediates with compounds III.a or III.b., which can be easily eliminated to compounds of the general formula X.1 to X.3.

[0330] Diene compounds of the general formula X.1 to X.3 can also be reacted with compound (II) in step b). However, this reaction is very slow compared to the reaction with compounds III.a or III.b. The formation of diene compounds X.1 to X.3 should therefore be avoided.

[0331] In addition, as shown in Scheme 5, the reaction of hydroquinone compound (II) with compound III.a may form a benzofuran isomer of formula XI-1, which is difficult to separate from the desired condensation product.

[0332] Solution 5:

[0333]

[0334] By using the method of the present invention, the formation of these common by-products can be successfully suppressed.

[0335] The following examples provide further explanation of the present invention. These examples should not be construed as limiting the present invention.

[0336] Example

[0337] Abbreviations:

[0338] GC stands for gas chromatography,

[0339] HPLC High Performance Liquid Chromatography,

[0340] TMH stands for trimethylhydroquinone (2,3,5-trimethylhydroquinone),

[0341] TMQ stands for trimethylquinone (2,3,5-trimethylquinone),

[0342] PC Propylene Carbonate

[0343] EC Ethylene carbonate

[0344] 1. Analysis:

[0345] 1.1 Determination of product purity:

[0346] The purity of the product was determined by gas chromatography area %. The yields of compounds I and II were determined by GC wt % using behenic acid as internal standard and n-heptane as solvent.

[0347] GC system: Agilent 6980N;

[0348] GC-column: Agilent DB-1: 30 m (length), 0.25 mm (inner diameter), 0.25 μm (film thickness);

[0349] Temperature program: 80°C to 350°C at 10° / min, 350°C for 10 minutes, total run time: 37 minutes

[0350] The amount of compound (III) in the (final) reaction mixture was determined by HPLC - wt %:

[0351] HPLC system: Agilent 1200 series

[0352] HPLC column: Zorbax Eclipse PAH, 1.8 μm, 50*4.6 mm von Agilent

[0353] Eluent:

[0354] A: Water containing 0.1 volume % H3PO4

[0355] B: Acetonitrile

[0356] Time [minutes] ％B 0.0 5 3.0 15 10.0 100 17.0 100 17.1 5

[0357] Detector: UV-detector λ=210 nm, BW=5 nm, flow rate: 1.2 mL / min, injection: 2 μL, temperature: 60°C, run time: 20 min, pressure: about 130 bar

[0358] 1.2 Determination of BET surface area:

[0359] System: Quantachrome Autosorb automatic gas adsorption system 6B, serial number: 10896010901;

[0360] Software: Autosorb for AS-3 and AS-6 Version 1.22

[0361] Sample weight: 0.28-0.43 g of solid catalyst (e.g. treated bentonite catalyst);

[0362] Bath temperature: 77.4K;

[0363] Running time: 64-106.7 minutes;

[0364] Gas used for measurement: Nitrogen; Gas purity: Nitrogen 5.0;

[0365] Drying before measurement: 16 h at 120 °C, < 1 mbar, by means of a rotary vane pump and finally a turbomolecular pump;

[0366] System parameters: Cross-sectional area

[0367] Multi-point BET: 5 points p / p o; 0.05≤p / p o ≤0.30.

[0368] 1.3 Determination of residual acidity of solid catalyst (mg KOH / g solid catalyst):

[0369] The residual acidity of a solid catalyst (e.g., a treated bentonite catalyst) is determined in the following manner: First, an aqueous suspension having a certain amount of solid catalyst is prepared as follows: 1.0 g to 1.5 g of the solid catalyst is suspended in 50 mL of deionized water and stirred for 1 h. A previously calibrated KCl-pH electrode is placed in this suspension. Then an aqueous NaOH solution having a defined concentration of 0.1 mol / L is titrated into the aqueous suspension until the pH value of the suspension of the solid catalyst switches to the alkaline range (inflection point), which represents the end point of the titration. The volume V1 in mL of the NaOH solution used to reach the inflection point is recorded.

[0370] In addition, a blank measurement was performed in the same manner using 50 mL of deionized water. The volume V2 of the NaOH solution used in mL was recorded.

[0371] The residual acidity (in mg KOH / g solid catalyst) of the solid catalyst sample, determined as the total acid number, was then calculated based on the following formula:

[0372]

[0373] 56.1 g / mol represents a constant (molar mass of KOH in g / mol);

[0374] m1 is the mass of the test portion (i.e., the solid catalyst sample) in grams;

[0375] V1 is the volume in milliliters of the NaOH solution used to neutralize the catalyst suspension (the volume until the inflection point is reached);

[0376] V2 is the volume in milliliters of the NaOH solution used for the blank determination (volume until the inflection point is reached – usually no volume is consumed / blank is usually zero);

[0377] C is the concentration of NaOH solution in mol / L;

[0378] t is the titer of NaOH solution.

[0379] The determination of the residual acidity was repeated once and was therefore determined twice.

[0380] 1.4 Determination of catalyst density:

[0381] Machine: Pycnometer series AccuPyc II 1340

[0382] Company: Micromeritics

[0383] Inert gas: Helium

[0384] Sample weight: 2.1-4.8g

[0385] Sample chamber: 10mL

[0386] The program "Analysis Conditions" was used, comprising 99 cycles, each with 5 replicates.

[0387] Prior to the measurements, the samples were treated at 120 °C, <1 mbar vacuum for 16 h.

[0388] Density [g / ccm] = sample mass [g] / sample volume [ccm]

[0389] 1. Preparation Example

[0390] Source and specification of the acid-treated bentonite catalyst used:

[0391] The acid-treated bentonite used as catalyst in the following preparation examples was either an in-house developed acid-treated bentonite from BASF SE (BASF SE in-house material) or an acid-treated bentonite commercially available from Sigma Aldrich or Clariant Produkte GmbH.

[0392] The following bentonite catalyst specifications were used:

[0393]

[0394] *) Determined by Karl-Fischer titration and / or by weight loss after drying (drying at 120° C. and a pressure of <1 mbar for 16 h).

[0395] To prepare the acid-treated bentonite catalysts (catalysts 1 to 5) from BASF SE, Aberdeen clays, known for their high quality, were used as natural bentonite starting materials. These bentonites were activated using sulfuric acid and then converted into the final granular mineral catalysts.

[0396] General reaction procedures and comments:

[0397] The progress of the reaction was monitored by TLC and GC.

[0398] Step 1: Restore TMQ to TMH

[0399] Step 2: Friedel-Crafts alkylation and condensation

[0400] Unless otherwise stated, all reactions were performed in glass flasks with a paddle stirrer and a Dean-Stark trap.

[0401] - If a mixture of HS and PS is used as solvent, it is filled with the HS used,

[0402] - if PS is used as a solvent that does not form an azeotrope with water, leave this blank, and

[0403] If a solvent is used which forms an azeotrope with water, the filling is with the solvent used (different from water) which is removed azeotropically with water.

[0404] Step 3: Esterification

[0405] 2.1 Preparation of 2,3,5-trimethylhydroquinone (Step 1)

[0406] 4 g of 2,3,5-trimethylquinone (99.6%, 26.5 mmol) was dissolved in 76 g (63.1 mL) of propylene carbonate at room temperature. 0.4 g of palladium charcoal (10%, 0.38 mmol, 0.01 eq.) was added, and the resulting reaction mixture was hydrogenated at 8 bar of hydrogen pressure and 64° C. for 23 hours. After a reaction time of 6 hours, the filtered reaction mixture was only a slightly yellow solution, and after a reaction time of 23 hours, a colorless solution. The following GC analysis was obtained:

[0407] 2.2 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (steps 1 and 2):

[0408] Preparation of 2,3,5-trimethylhydroquinone

[0409] 14 g of 2,3,5-trimethylquinone (99.6%, 92.85 mmol) was dissolved in 79.3 g (65.9 mL) of propylene carbonate at room temperature. 2.8 g of palladium charcoal (10%, 2.6 mmol, 0.03 eq.) was added, and the resulting reaction mixture was hydrogenated at 8 bar of hydrogen pressure and 88° C. for 23 hours. Then, the reaction mixture was immediately filtered to obtain 83.3 g of an almost colorless eluent (97.6 GC-a% TMH and 0.05 GC-a% TMQ).

[0410] Preparation of all-racemic α-tocopherol (catalyst 2):

[0411] 0.19 g of catalyst 2 (dried overnight in a vacuum oven at 120° C. / 50 mbar) / g of TMH (2.7 g of catalyst 2) was added to the crude TMH in propylene carbonate (81.4 g after analysis, assumed: 100% yield: 92.85 mmol, 1.7 eq.). The reaction mixture was brought to 120-125° C. and stirred for 15 minutes. Then, 16.45 g of isophytol (97.4%, 54 mmol) was added continuously to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 120-125° C.), while the water formed during the reaction was removed by distillation. After 4 hours at 125° C., overnight at room temperature, and then a further reaction time of 4 hours at 125° C., the reaction mixture was brought to room temperature, 20 mL of heptane was added, it was further stirred for 15 minutes, and then filtered through celite to remove catalyst 2. The filter cake was washed with 6*20 mL of heptane and 3*20 mL of propylene carbonate. After phase separation, propylene carbonate phase was extracted with 4*25mL heptane. The combined heptane phase was dried over sodium sulfate. Solvent was removed under reduced pressure 50 ℃ / 5 mbar plus oil pump vacuum for 15 minutes. 24.09g of crude α-tocopherol (91.6GC area % and 85.66GC weight %) (based on the GC weight percentage of two steps) in the form of dark red clear viscous residue was obtained in 89% yield. Each step had an average yield of 94.5% yield.

[0412] 2.3 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 1):

[0413] 233.57g (193.99mL) propylene carbonate and 0.22g catalyst 1 (dried overnight at 120°C, 50 mbar) / g TMH (21.75g ​​catalyst 1) were heated to 120-125°C under a nitrogen stream and stirred for 15 minutes. The suspension was then cooled to <90°C and 100.11g (652.5mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to 120-125°C again. Then 136.35g (162.13mL) isophytol (447.9mmol, 97.4% purity, 1 equivalent) was continuously added to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 120-125°C), while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 120-125°C, the reaction mixture was cooled to room temperature. The mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 1. The filter cake was washed with 6*130 mL heptane and 3*130 mL propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*190 mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50-55° C. / 5 mbar plus 15 minutes oil pump vacuum: 200 g of crude α-tocopherol (94.6 GC area % and 94.53 GC weight %) in the form of a dark red clear viscous residue was obtained. This is equivalent to a yield of 98%.

[0414] 2.4 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 1):

[0415] 138.08g (141.91mL) ethylene carbonate and 0.22g catalyst 1 (dried overnight at 120°C, 50 mbar) / g TMH (7.5g catalyst 1) were heated to 120-123°C under nitrogen flow and stirred for 15 minutes. The suspension was then cooled to <90°C and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to 120-125°C again. Then 45.76g (54.41mL) isophytol (150mmol, 97.2% purity, 1 equivalent) was added continuously to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 124-119°C), while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 120-125°C, the reaction mixture was cooled to room temperature. 45mL heptane was added to the reaction mixture, which was stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 1. The filter cake was washed with 6*45 mL of heptane. All mother liquors and washings were collected and combined. The eluent in which precipitation was observed was subsequently filtered and the solvent was removed under reduced pressure at 50-55° C. / 5 mbar plus 15 minutes of oil pump vacuum: 68.84 g of crude α-tocopherol (84.8 GC area % and 78.79 GC weight %) were obtained in the form of a brown-red viscous turbid residue. This corresponds to a yield of 84%.

[0416] 2.5 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 1):

[0417] 80.55g (71.92mL) of γ-butyrolactone and 0.22g of catalyst 1 (dried overnight at 120°C, 50 mbar) / gTMH (7.5g of catalyst 1) were heated to 120-125°C under a nitrogen stream and stirred for 15 minutes. The suspension was then cooled to <90°C and 34.52g (225mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 120-125°C again. Then 45.76g (54.3mL) of isophytol (150mmol, 97.4% purity, 1 equivalent) was added continuously to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 120-125°C), while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 120-125°C, the reaction mixture was cooled to room temperature. 45mL of heptane was added to the reaction mixture, which was stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 1. The filter cake was washed with 6*45 mL of heptane and 3*45 mL of γ-butyrolactone. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The γ-butyrolactone phase was extracted with 4*65 mL of heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50-55° C. / 5 mbar plus 15 minutes of oil pump vacuum: 68.71 g of crude α-tocopherol (89.7 GC area % and 78.38 GC weight %) were obtained in the form of a dark red clear viscous residue. This corresponds to a yield of 83%.

[0418] 2.6 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 1):

[0419] The reaction was carried out without water removal and therefore without a Dean stark trap. The equipment used consisted of a flask, a blade stirrer and a reflux condenser.

[0420] 80.55g (66.9mL) propylene carbonate and 0.22g catalyst 1 (dried overnight at 120°C, 50 mbar) / gTMH (7.5g catalyst 1) were heated to 120-125°C and stirred for 15 minutes under a nitrogen stream. The suspension was then cooled to <90°C and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to 120-125°C again. Then 45.86g (54.5mL) isophytol (150mmol, 97% purity, 1 equivalent) was added continuously to the reaction mixture over a 2-hour period (temperature of the reaction mixture: 120-125°C). At 123-124°C for 4 hours, overnight at room temperature, and after a further reaction time of another 2 hours at 124°C, the reaction mixture was cooled to room temperature. 45mL heptane was added to the reaction mixture, which was stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 1. The filter cake was washed with 6*45mL heptane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50-55°C / 5 mbar plus 15 minutes oil pump vacuum: 66.04g of crude α-tocopherol (92.7GC area % and 84.55GC weight %) were obtained in the form of a dark red clear viscous residue. This is equivalent to a yield of 86%.

[0421] 2.7 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 2):

[0422] 103.14 g (78.08 mL) of ethylene carbonate, 47.73 g (67.9 mL) of n-octane (plus 60 mL of octane in a dean-stark trap) and 0.65 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (22.5 g of catalyst 2) were heated to slight n-octane reflux (temperature of the reaction mixture: 120-125° C.) under a nitrogen stream and stirred for 15 minutes under reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 120° C. again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 120-125° C.) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 123-126°C, the reaction mixture was cooled to <60°C and 50g of propylene carbonate was added. Then, the reaction mixture was further cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45mL octane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The ethylene carbonate / propylene ester phase was extracted with 4*65mL octane. The combined octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50-55°C / 5 mbar plus 15 minutes of oil pump vacuum: 63.66g of crude α-tocopherol (95.5GC area % and 91.44GC weight %) in the form of a dark red clear viscous residue were obtained. This is equivalent to a yield of 90%.

[0423] 2.8 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 2):

[0424] 232.63 g (193.21 mL) of propylene carbonate, 118.06 g (167.9 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.22 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (21.75 g of catalyst 2) were heated to a slight n-octane reflux (temperature of the reaction mixture: 120-125° C.) under a nitrogen stream and stirred at reflux for 15 minutes. The suspension was then cooled to <80° C. and 99.7 g (625.5 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 123° C. again. Then in the time period of 2 hours, 137.22g (163.17mL) of isophytol (435mmol, 94% purity, 1 equivalent) is continuously added in the reaction mixture (temperature of the reaction mixture: 125-123 ℃), and the water formed during the reaction is removed by distillation. After 4 hours at 123-125 ℃, spending the night at room temperature, and after the further reaction time of another 2 hours at 125 ℃, the reaction mixture is cooled to room temperature and filtered to remove catalyst 2 by a glass suction filter D4 equipped with diatomaceous earth. Wash the filter cake with 3*130mL heptane and 3*130mL propylene carbonate. Collect and combine all mother liquors and washings. The phase of the eluent is separated. Extract the propylene carbonate phase with 4*190mL heptane. The combined heptane / n-octane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50-55° C. / 5 mbar plus 15 minutes oil pump vacuum: 199.16 g of crude α-tocopherol (92.6 GC area % and 87.57 GC weight %) were obtained as a dark red, clear, viscous residue. This corresponds to a yield of 93%.

[0425] 2.9 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 2):

[0426] 80.55g (66.9mL) propylene carbonate and 0.22g catalyst 2 (at 120 ℃, dried overnight under 50 mbar) / gTMH (7.5g catalyst 2) are heated to 50-90 ℃ under nitrogen stream and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) are added. Then the mixture is heated to 150 ℃ and 45.67g (54.3mL) isophytol (150mmol, 97.4% purity, 1 equivalent) is added continuously in the reaction mixture in the time period of 2 hours. After the further reaction time of 6 hours, the reaction mixture is cooled to room temperature. 45mL heptane is added in the reaction mixture, and it is stirred at room temperature for 15 minutes. Then, the mixture is filtered to remove catalyst 2 by the glass suction filter D4 equipped with diatomite. The filter cake is washed with 6*45mL heptane and 3*45mL propylene carbonate. Collect and merge all mother liquors and washings. The phase of eluent is separated. The propylene carbonate phase was extracted with 4*65 mL of heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50° C. / 5 mbar plus an oil pump vacuum for 15 minutes: 65.61 g of crude α-tocopherol (92.5 GC area % and 84.73 GC weight %) were obtained as a dark red, clear, viscous residue. This corresponds to a yield of 86%.

[0427] 2.10 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 2):

[0428] 80.55g (66.9mL) propylene carbonate and 0.33g catalyst 2 (dried overnight at 120 ℃, 50 mbar) / gTMH (11.25g catalyst 2) are heated to 120-125 ℃ and stirred for 15 minutes under nitrogen flow. The suspension is then cooled to <90 ℃, and 34.52g (225mmol) trimethylhydroquinone (3 equivalents) are added. The mixture is then heated to 120-125 ℃ again. Then 22.88g (27.21mL) isophytol (75mmol, 97.2% purity, 1 equivalent) is continuously added to the reaction mixture (temperature of the reaction mixture: 121-125 ℃) over a period of 1 hour. After a further reaction time of 6 hours at 120-125 ℃, the reaction mixture is cooled to room temperature. 45mL heptane is added to the reaction mixture, which is stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 6*45mL heptane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50°C / 5 mbar plus 15 minutes oil pump vacuum: 33.99g of crude α-tocopherol (95.2GC area % and 88.45GC weight %) in the form of a dark red clear viscous residue was obtained. This is equivalent to a yield of 93%.

[0429] 2.11 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 2):

[0430] 80.55 g (66.9 mL) of propylene carbonate, 39.79 g (58.18 mL) of n-heptane (plus 60 mL of heptane in the dean-stark trap) and 0.22 g of catalyst 2 (dried overnight at 120 ° C, 50 mbar) / g of TMH (7.5 g of catalyst 2) were heated to a slight n-heptane reflux (temperature of the reaction mixture: 100 ° C) under a nitrogen stream and stirred for 15 minutes under reflux. The suspension was then cooled to <80 ° C and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 100 ° C again. Then 45.86 g (54.52 mL) of isophytol (150 mmol, 97% purity, 1 equivalent) was continuously added to the reaction mixture (temperature of the reaction mixture: 100-102 ° C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After 6 hours at 103-104° C., overnight at room temperature, and a further reaction time of 2 hours at 102° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45 mL heptane and 3*45 mL propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL heptane. The combined heptane / n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50° C. / 5 mbar plus 15 minutes oil pump vacuum: 63.99 g of crude α-tocopherol (88.9 GC area % and 85.26 GC weight %) were obtained in the form of a dark red clear viscous residue. This corresponds to a yield of 84%.

[0431] 2.12 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 3):

[0432] 80.55g (66.9mL) propylene carbonate and 0.22g catalyst 3 (dried overnight at 120°C, 50 mbar) / gTMH (7.5g catalyst 3) were heated to 120-125°C and stirred for 15 minutes under nitrogen flow. The suspension was then cooled to <90°C and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to 120-125°C again. Then 45.86g (54.52mL) isophytol (150mmol, 97% purity, 1 equivalent) was added continuously to the reaction mixture over a 2-hour period (temperature of the reaction mixture: 122-125°C). At 120-125°C for 4 hours, at room temperature over the weekend, and at 120-125°C for another 2 hours of further reaction time, the reaction mixture was cooled to room temperature. 45mL heptane was added to the reaction mixture, which was stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 3. The filter cake was washed with 6*45mL heptane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50°C / 5 mbar plus 15 minutes oil pump vacuum: 65.43g of crude α-tocopherol (94.1GC area % and 87.05GC weight %) were obtained in the form of a dark red clear viscous residue. This is equivalent to a yield of 88%.

[0433] 2.13 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 4):

[0434] 80.22 g (66.63 mL) of propylene carbonate, 40.71 g (57.91 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.65 g of catalyst 4 (dried overnight at 120° C., 50 mbar) / g of TMH (22.5 g of catalyst 4) were heated to slight n-octane reflux (temperature of the reaction mixture: 120-122° C.) under a nitrogen stream and stirred for 15 minutes under reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 120° C. again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 118-120° C.) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 121-124° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 4. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus an oil pump vacuum for 15 minutes: 64.06 g of crude α-tocopherol (90.5 GC area % and 86.86 GC weight %) were obtained in the form of a dark red, clear, viscous residue. This corresponds to a yield of 86%.

[0435] 2.14 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 5):

[0436] 80.22 g (66.63 mL) of propylene carbonate, 40.71 g (57.91 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.65 g of catalyst 5 (dried overnight at 120° C., 50 mbar) / g of TMH (22.5 g of catalyst 5) were heated to slight n-octane reflux (temperature of the reaction mixture: 120-121° C.) under a nitrogen stream and stirred at reflux for 15 minutes. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 120° C. again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 115-120° C.) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After 4 hours at 119-123° C., at room temperature over the weekend, and at 122° C. for another 2 hours of further reaction time, the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 5. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus 15 minutes of oil pump vacuum: 65.08 g of crude α-tocopherol (87.3 GC area % and 85.15 GC weight %) were obtained in the form of a dark red clear viscous residue. This corresponds to a yield of 86%.

[0437] 2.15 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 6):

[0438] 80.55g (66.9mL) propylene carbonate and 0.33g catalyst 6 (undried) / g TMH (11.25g catalyst 6) are heated to 120-125 ℃ and stirred for 15 minutes under nitrogen flow. The suspension is then cooled to <90 ℃, and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) is added. The mixture is then heated to 120-125 ℃ again. Then 45.67g (54.3mL) isophytol (150mmol, 97.4% purity, 1 equivalent) is added continuously to the reaction mixture (temperature of the reaction mixture: 122-125 ℃) over a period of 1 hour. After a further reaction time of 6 hours at 122-125 ℃, the reaction mixture is cooled to room temperature. 45mL heptane and diatomaceous earth are added to the reaction mixture, which is stirred at room temperature for 15 minutes. Then, the mixture is filtered through a glass suction filter D4 to remove catalyst 6. The filter cake was washed with 6*45mL heptane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50°C / 5 mbar for 15 minutes under an oil pump vacuum: 64.75g of crude α-tocopherol (86.7GC area % and 81.19GC ​​weight %) in the form of a dark red clear viscous residue was obtained. This is equivalent to a yield of 81%.

[0439] 2.16 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 7):

[0440] 80.55g (66.9mL) propylene carbonate and 0.33g catalyst 7 (undried) / g TMH (11.25g catalyst 7) ​​are heated to 120-122 ℃ and stirred for 15 minutes under nitrogen flow. The suspension is then cooled to <90 ℃, and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) is added. The mixture is then heated to 120-125 ℃ again. Then 45.67g (54.3mL) isophytol (150mmol, 97.4% purity, 1 equivalent) is added continuously to the reaction mixture (temperature of the reaction mixture: 120-124 ℃) over a period of 1 hour. After a further reaction time of 6 hours at 120-125 ℃, the reaction mixture is cooled to room temperature. 45mL heptane is added to the reaction mixture, which is stirred at room temperature for 15 minutes. Then, the mixture is filtered to remove catalyst 7 by a glass suction filter D4 equipped with diatomaceous earth. The filter cake was washed with 6*45mL heptane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50°C / 5 mbar for 15 minutes under an oil pump vacuum: 64.76g of crude α-tocopherol (91.8GC area % and 86.01GC weight %) in the form of a dark red clear viscous residue was obtained. This is equivalent to a yield of 86%.

[0441] 2.17 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 8):

[0442] 80.55g (66.9mL) propylene carbonate and 0.44g catalyst 8 (undried) / g TMH (15g catalyst 8) are heated to 120°C and stirred for 15 minutes under nitrogen flow. The suspension is then cooled to <90°C and 34.52g (225mmol) trimethylhydroquinone (1.5 equivalents) are added. The mixture is then heated to 120-125°C again. Then 45.67g (54.3mL) isophytol (150mmol, 97.4% purity, 1 equivalent) is added continuously to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 121-125°C). At 121-125°C for 4 hours, overnight at room temperature, and after a further reaction time of another 2 hours at 120-125°C, the reaction mixture is cooled to room temperature. 45mL heptane is added to the reaction mixture, which is stirred at room temperature for 15 minutes. Then, the mixture was filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 8. The filter cake was washed with 6*45mL heptane and 4*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL heptane. The combined heptane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 50°C / 5 mbar plus 15 minutes oil pump vacuum: 64.27g of crude α-tocopherol (75.8GC area % and 87.13GC weight %) were obtained in the form of a dark red clear viscous residue. This is equivalent to a yield of 87%.

[0443] 2.18 Preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (Step 2; Catalyst 9):

[0444] 80.55 g (66.9 mL) of propylene carbonate and 0.33 g of catalyst 9 (undried) / g TMH (11.25 g of catalyst 9) were heated to 120° C. under a nitrogen stream and stirred for 15 minutes. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated again to 120-125° C. 45.67 g (54.3 mL) of isophytol (150 mmol, 97.4% purity, 1 equivalent) were then added continuously to the reaction mixture over a period of 1 hour (temperature of the reaction mixture: 123-125° C.). After a further reaction time of 6 hours at 125° C., the reaction mixture was analyzed. 30 GC-area% TMH, 5 GC-area% phytadiene, 19 GC-area% Phytyl-TMH, no α-tocopherol. The reaction mixture was discarded.

[0445] 2.19 Continuous preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol) (step 2; catalyst 9):

[0446] Catalyst used:

[0447] Montmorillonite K10 (pH 3-4, surface area) from Thales Nano "diluted" with diatomaceous earth in a mass ratio of 1:1 filled into cartridges (so-called CatCarts). The CatCar cartridges used had dimensions of 70 x 4 mm and a filling mass of 459 mg.

[0448] Continuous preparation process:

[0449] An 8 wt. % solution of TMH in bis(2-methoxyethyl) ether (= diglyme) and a 10.4 wt. % solution of isophytol in bis(2-methoxyethyl) ether (= diglyme) were pumped at a volume flow of 5 mL / h onto the above-mentioned CatCart with K10 and diatomaceous earth and heated to 200° C. The catalyst CatCart was placed in a vertical position.

[0450] The progress of the reaction was monitored by GC: 61.3 GC area % of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (all-racemic α-tocopherol), 19.4 GC area % of TMH and 13.5 GC area % of phytadiene were obtained.

[0451] 2.20 Preparation of all-racemic α-tocopherol acetate (steps 1, 2 and 3):

[0452] Preparation of 2,3,5-trimethylhydroquinone

[0453] 14 g of 2,3,5-trimethylquinone (99.6%, 92.85 mmol) was dissolved in 79.7 g (66.2 mL) of propylene carbonate at room temperature. 2.8 g of palladium charcoal (10%, 2.63 mmol, 0.03 eq.) was added, and the resulting reaction mixture was hydrogenated at 8 bar of hydrogen pressure and 87-93° C. for 22.5 hours. The reaction mixture was filtered at room temperature and nitrogen using a warm glass suction filter D4 with a paper filter, and 84.31 g of eluent (95.3 GC area % trimethylhydroquinone and 0.28 GC-a % trimethylquinone) were obtained.

[0454] Preparation of all-racemic α-tocopherol (catalyst 2):

[0455] To the crude trimethylhydroquinone in propylene carbonate obtained in the first step (82.83 g, 1.73 equivalents, assuming 100% yield, 92.85 mmol) was added 0.19 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (2.69 g of catalyst 2), heated to 120° C. and stirred at 120-124° C. for 15 minutes. Then 16.38 g (19.47 mL) of isophytol (53.8 mmol, 97.4% purity, 1 equivalent) was added continuously to the reaction mixture over a period of 2 hours (temperature of the reaction mixture: 124-125° C.), while the water formed during the reaction was removed by distillation. After a further reaction time of 5 hours at 125° C., the reaction mixture was stirred at room temperature overnight.

[0456] Preparation of all-racemic α-tocopherol acetate (catalyst 2):

[0457] The brown suspension obtained from the second step is heated to 50°C, and 22.19g (20.55mL) of acetic anhydride (220mmol, 4 equivalents) is added continuously over a period of 15 minutes. Then, the reaction mixture is heated to 100°C and stirred for 4 hours. After cooling to room temperature, 20mL of heptane is added to the reaction mixture, which is stirred for 15 minutes. Then, the reaction mixture is filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake is washed with 6*20mL heptane and 3*20mL propylene carbonate. All mother liquors and washings are collected and combined. The phase of the eluent is separated. The propylene carbonate phase is extracted with 4*25mL heptane. The combined heptane phases are dried over sodium sulfate, and volatiles are removed under reduced pressure at 50°C / 5 mbar plus 15 minutes of oil pump vacuum: 25.71g of crude all-racemic α-tocopherol acetate (89.28GC area %) in the form of a brown clear viscous residue is obtained. This corresponds to a 90% yield (GC area % based on 3 steps).

[0458] 2.21 Preparation of all-racemic α-tocopherol acetate (steps 2 and 3):

[0459] Preparation of all-racemic α-tocopherol (catalyst 2):

[0460] Add 100.29g (83.3mL) propylene carbonate and 35.15g catalyst 2, be heated to 120-125 ℃ and stir 15 minutes.Then the suspension is cooled to<90 ℃, and 22.92g (150mmol) trimethylhydroquinone (1.0 equivalent) is added.Then the mixture is heated to 120 ℃ again.Then in the time period of 2 hours, 46.75g (55.59mL) isophytol (154.5mmol, 98% purity, 1.03 equivalent) is added continuously in the reaction mixture (temperature of reaction mixture: 120-123 ℃), and the water formed during the reaction is removed by distillation simultaneously.After the further reaction time of 4 hours at 123-124 ℃, the reaction mixture is stirred at room temperature over the weekend.

[0461] Preparation of all-racemic α-tocopherol acetate (catalyst 2):

[0462] To the brown suspension obtained from the previous step, 30.94g (28.64mL) of acetic anhydride (300mmol, 2 equivalents) was added continuously over a period of 10 minutes. Then, the reaction mixture was reactively distilled for 2 hours (500 mbar, internal temperature 87-92°C, transition temperature 28-33°C, oil bath temperature 100°C). Then, the reaction mixture was returned to room temperature and 45mL of heptane was added, and the reaction mixture was stirred for 15 minutes. Then, it was filtered through a glass suction filter D4 to remove catalyst 2. The filter cake was washed with 3*45mL of heptane and 3*45mL of propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles removed under reduced pressure at 50° C. / 5 mbar plus 15 minutes oil pump vacuum: 71.79 g of crude all-racemic α-tocopheryl acetate (88.08 GC area %) containing 0.18 GC area % α-tocopherol were obtained as a brown, clear, viscous residue. This corresponds to a yield of 89% (GC area % based on 2 steps).

[0463] 2.22 Effect of drying temperature of bentonite catalyst:

[0464] The effect of drying the bentonite catalyst before using it in the condensation reaction of TMH and IP was evaluated. Two reactions were carried out similarly to Example 2.8, except that 225 mmol TMH was used instead of 625.5 mmol TMH (the amounts of the other reactants were adjusted accordingly). The results are summarized in Table 1.

[0465] Table 1: Effect of drying temperature of bentonite catalyst 2 on α-tocopherol yield

[0466]

[0467] In the bentonite-catalyzed reaction of TMH with IP, drying the bentonite catalyst prior to use can increase the catalyst conversion under the reaction conditions employed therein (eg, the PC / octane solvent mixture employed).

[0468] As the drying temperature of bentonite catalyst 2 increased, the yield of α-tocopherol increased from 79% (undried catalyst 2) to 93% (catalyst 2, dried overnight at 120° C., 50 mbar, vacuum oven).

[0469] Example 2.22.1:

[0470] Preparation of fully racemic α-tocopherol:

[0471] 80.22 g (66.6 mL) of propylene carbonate, 40.71 g (57.91 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.74 g of catalyst 2 (undried as is) / g of TMH (25.43 g of catalyst 2) were heated to slight reflux (temperature of the reaction mixture: 109 ° C) under a nitrogen stream and stirred for 15 minutes under reflux. The suspension was then cooled to <80 ° C and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to slight reflux at 113 ° C again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 113-112 ° C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 118-123° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus an oil pump vacuum for 15 minutes: 59.31 g of crude α-tocopherol (89.7 GC area % and 85.47 GC weight %) were obtained in the form of a dark red, clear, viscous residue. This corresponds to a yield of 79%.

[0472] Example 2.22.2:

[0473] Preparation of fully racemic α-tocopherol:

[0474] 80.22g (66.6mL) propylene carbonate, 40.71g (57.91mL) n-octane (plus 60mL octane in dean-stark water trap) and 0.65g catalyst 2 (dried overnight at 60°C, 50 mbar) / g TMH (22.5g catalyst 2) were heated to slight reflux (temperature of reaction mixture: 115-117°C) under nitrogen flow and stirred at reflux for 15 minutes. The suspension was then cooled to <80°C and 34.38g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to slight reflux at 118°C again. 45.39g (53.97mL) isophytol (150mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of reaction mixture: 119-117°C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 120-124° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus an oil pump vacuum for 15 minutes: 61.10 g of crude α-tocopherol (91.1 GC area % and 86.31 GC weight %) were obtained in the form of a dark red, clear, viscous residue. This corresponds to a yield of 82%.

[0475] Example 2.22.3:

[0476] Preparation of fully racemic α-tocopherol:

[0477] 80.22g (66.6mL) propylene carbonate, 40.71g (57.91mL) n-octane (plus 60mL octane in dean-stark water trap) and 0.65g catalyst 2 (dried overnight at 100°C, 50 mbar) / g TMH (22.5g catalyst 2) were heated to slight reflux (temperature of reaction mixture: 120-121°C) under nitrogen flow and stirred at reflux for 15 minutes. The suspension was then cooled to <80°C and 34.38g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to slight reflux at 122°C again. Then 45.39g (53.97mL) isophytol (150mmol, 98% purity, 1 equivalent) was continuously added to the reaction mixture (temperature of reaction mixture: 122-121°C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 123-125° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus 15 minutes of oil pump vacuum: 65.91 g of crude α-tocopherol (92.1 GC area % and 86.47 GC weight %) were obtained in the form of a dark red clear viscous residue. This corresponds to a yield of 88%.

[0478] Example 2.22.4:

[0479] Preparation of fully racemic α-tocopherol:

[0480] 80.22g (66.6mL) propylene carbonate, 40.71g (57.91mL) n-octane (plus 60mL octane in dean-stark water separator) and 0.65g catalyst 2 (dried overnight at 120°C, 50 mbar) / g TMH (22.5g catalyst 2) were heated to slight reflux (temperature of reaction mixture: 120-121°C) under nitrogen flow and stirred at reflux for 15 minutes. The suspension was then cooled to <80°C and 34.38g (225mmol) trimethylhydroquinone (1.5 equivalents) was added. The mixture was then heated to slight reflux at 121°C again. Then 45.39g (53.97mL) isophytol (150mmol, 98% purity, 1 equivalent) was continuously added to the reaction mixture (temperature of reaction mixture: 115-121°C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 6 hours at 118-123° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45 mL of n-octane and 3*45 mL of propylene carbonate. All mother liquors and washings were collected and combined. The phases of the eluent were separated. The propylene carbonate phase was extracted with 4*65 mL of n-octane. The combined n-octane phases were dried over sodium sulfate and volatiles were removed under reduced pressure at 55° C. / 5 mbar plus an oil pump vacuum for 15 minutes: 68.47 g of crude α-tocopherol (91.2 GC area % and 87.93 GC weight %) were obtained in the form of a dark red, clear, viscous residue. This corresponds to a yield of 93%.

[0481] 2.23 Recovering the bentonite catalyst in step 2:

[0482] The possibility of recycling bentonite catalysts used in Friedel-Crafts alkylation and condensation reactions was evaluated. Several reactions were performed as described below (Example 2.23.1) where bentonite catalyst 2 was recovered in each reaction and reused in the same subsequent reactions.

[0483] Under otherwise identical conditions, the recycling of bentonite catalyst 2 showed a five-fold increase for Friedel-Crafts alkylation and condensation reactions (see Examples 2.23.1 to 2.23.6 in Table 2). The yields were reproducible within the error range.

[0484] Table 2: Recovery of Bentonite Catalyst 2

[0485] Example No.: entry: α-Tocopherol yield [%] 2.23.1. 1 86 2.23.2. 2 87 2.23.3. 3 89 2.23.4. 4 87 2.23.5. 5 90 2.23.6. 6 89

[0486] Example 2.23.1:

[0487] Preparation of fully racemic α-tocopherol:

[0488] 80.22 g (66.63 mL) of propylene carbonate, 40.71 g (57.91 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.65 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (22.5 g of catalyst 2) were heated to a slight n-octane reflux (temperature of the reaction mixture: 120-121° C.) under a nitrogen stream and stirred at reflux for 15 minutes. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 121° C. again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 116-121° C.) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After 4 hours at 120-122° C., overnight at room temperature, and a further reaction time of 2 hours at 122° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 to remove catalyst 2. The filter cake was washed with 3*45 mL n-octane and 3*45 mL propylene carbonate. The residue was sucked dry and further dried overnight in a nitrogen stream (wet weight: 40.20 g, dry weight: 38.11 g). The bentonite catalyst 2 thus recovered was used again in Example 2.23.2.

[0489] Collect and combine all mother liquors and washings. The phase of the eluent is separated. Use 4*65mL n-octane to extract the propylene carbonate phase. The n-octane phase merged by sodium sulfate drying, and under reduced pressure at 55 ℃ / 5 mbar, add 15 minutes oil pump vacuum to remove volatiles: obtain 64.90g crude α-tocopherol (92.0GC area % and 86.02GC weight %) in the form of red clear viscous residue. This is equivalent to a yield of 86%.

[0490] Example 2.23.2:

[0491] Preparation of fully racemic α-tocopherol:

[0492] 80.22 g (66.63 mL) of propylene carbonate, 40.71 g (57.91 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 38.11 g of catalyst 2 from Example 2.23.1 were heated to a slight n-octane reflux (temperature of the reaction mixture: 120-124 ° C) under a nitrogen stream and stirred at reflux for 15 minutes. The suspension was then cooled to <80 ° C and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 122 ° C again. 45.39 g (53.97 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 119-122 ° C) over a period of 2 hours, while the water formed during the reaction was removed by distillation. After a further reaction time of 2 hours at 122° C., overnight at room temperature, and a further 4 hours at 123-124° C., the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 to remove catalyst 2. The filter cake was washed with 3*45 mL n-octane and 3*45 mL propylene carbonate. The residue was sucked dry and further dried over the weekend in a nitrogen stream (dry weight: 33.33 g). The bentonite catalyst 2 thus recovered was used again in Example 2.23.3.

[0493] Collect and merge all mother liquors and washings.The phase of eluent is separated.Extract propylene carbonate phase with 4*65mL heptane.By sodium sulfate drying combined heptane / n-octane phase, and under reduced pressure at 55 ℃ / 5 mbar add 15 minutes oil pump vacuum to remove volatile matter: obtain 65.62g crude α-tocopherol (92.6GC area % and 86.04GC weight %) of red clear viscous residue form.This is equivalent to 87% yield.

[0494] Examples 2.23.3–2.23.6 Proceed as described in Example 2.23.2.

[0495] 2.24 Recovery of bentonite catalyst in steps 2 and 3:

[0496] Example 2.24.1:

[0497] Preparation of fully racemic α-tocopherol:

[0498] Add 100.29g (83.3mL) propylene carbonate and 1.01g catalyst 2 (dried overnight at 120°C, 50 mbar) / g TMH (23.17g catalyst 2), heat to 123-124°C and stir for 15 minutes. Then the suspension is cooled to <90°C and 22.92g (150mmol) trimethylhydroquinone (1.0 equivalent) is added. Then the mixture is heated to 120°C again. Then 46.75g (55.59mL) isophytol (154.5mmol, 98% purity, 1.03 equivalent) is continuously added to the reaction mixture (temperature of the reaction mixture: 120-121°C) over a period of 2 hours, while the water formed during the reaction is removed by distillation. After a further reaction time of 4 hours at 120-125°C, the reaction mixture is stirred at room temperature overnight.

[0499] Preparation of fully racemic α-tocopherol acetate:

[0500] To the brown suspension obtained from the previous step, 30.94 g (28.64 mL) of acetic anhydride (300 mmol, 2 equivalents) was added continuously over a period of 10 minutes. Then, the reaction mixture was reactively distilled for 1 hour (310-335 mbar, internal temperature 74-88 ° C, transition temperature 28-45 ° C, oil bath temperature 100 ° C). The reaction mixture was stirred over the weekend at room temperature and atmospheric pressure. Then, the reaction mixture was further reactively distilled for 1 hour (310-335 mbar, internal temperature 64-67 ° C, transition temperature 32-34 ° C, oil bath temperature 75 ° C). Then, the reaction mixture was returned to room temperature and 45 mL of heptane was added, and the reaction mixture was stirred for 15 minutes. Then, it was filtered through a glass suction filter D4 to remove catalyst 2. The filter cake was washed with 3*45 mL of heptane and 3*45 mL of propylene carbonate. The residue was sucked dry and further dried for 3 days in a nitrogen stream (wet weight: 42.76 g, dry weight: 35.15 g). The bentonite catalyst 2 thus recovered was used again in Example 2.24.2.

[0501] Collect and merge all mother liquors and washings.The phase of eluent is separated.Extract propylene carbonate phase with 4*65mL heptane.By sodium sulfate drying combined heptane phase, and under reduced pressure at 50 ℃ / 5 mbar add 15 minutes oil pump vacuum to remove volatile matter: obtain 68.80g crude full racemic α-tocopherol acetate (79.90GC area %) in the form of yellow ochre clear viscous residue containing 8.34GC area % α-tocopherol.This is equivalent to 78% yield (based on 2 steps of GC area %).

[0502] Example 2.24.2:

[0503] Preparation of fully racemic α-tocopherol:

[0504] Add 100.29g (83.3mL) propylene carbonate and 35.15g of catalyst 2 from 2.24.1, be heated to 120-125 ℃ and stir for 15 minutes.Then the suspension is cooled to<90 ℃, and 22.92g (150mmol) trimethylhydroquinone (1.0 equivalent) is added.Then the mixture is heated to 120 ℃ again.Then in the time period of 2 hours, 46.75g (55.59mL) isophytol (154.5mmol, 98% purity, 1.03 equivalent) is added continuously in the reaction mixture (temperature of the reaction mixture: 120-123 ℃), and the water formed during the reaction is removed by distillation simultaneously.After the further reaction time of 4 hours at 123-124 ℃, the reaction mixture is stirred at room temperature over the weekend.

[0505] Preparation of fully racemic α-tocopherol acetate:

[0506] To the brown suspension obtained from the previous step, 30.94g (28.64mL) of acetic anhydride (300mmol, 2 equivalents) was added continuously over a period of 10 minutes. Then, the reaction mixture was reactively distilled for 2 hours (500 mbar, internal temperature 87-92°C, transition temperature 28-33°C, oil bath temperature 100°C). Then, the reaction mixture was returned to room temperature and 45mL of heptane was added, and the reaction mixture was stirred for 15 minutes. Then, it was filtered through a glass suction filter D4 to remove catalyst 2. The filter cake was washed with 3*45mL of heptane and 3*45mL of propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles removed under reduced pressure at 50° C. / 5 mbar plus 15 minutes oil pump vacuum: 71.79 g of crude all-racemic α-tocopheryl acetate (88.08 GC area %) containing 0.18 GC area % α-tocopherol were obtained as a brown, clear, viscous residue. This corresponds to a yield of 89% (GC area % based on 2 steps).

[0507] 2.25 Recovery of TMH used in excess in carbonate solvent:

[0508] The possibility of recycling the unreacted excess TMH and carbonate solution for Friedel-Crafts alkylation and condensation reactions was evaluated. Two reactions were carried out similarly to Example 2.8, except that 225 mmol TMH was used to replace 625.5 mmol TMH (the amounts of other reactants were adjusted accordingly), and the unreacted excess TMH was recovered in the carbonate solvent after the reaction was completed and reused in the following identical reactions. In both reactions, the yields obtained were the same (Examples 2.25.1 and 2.25.2 below, 87% yield in each case). Therefore, unreacted excess TMH can be successfully recycled with the carbonate solvent.

[0509] Example 2.25.1:

[0510] Preparation of fully racemic α-tocopherol:

[0511] 80.55 g (66.9 mL) of propylene carbonate, 40.9 g (58.18 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.22 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (7.5 g of catalyst 2) were heated to a slight n-octane reflux (temperature of the reaction mixture: 120-125° C.) under a nitrogen stream and stirred for 15 minutes under reflux. The suspension was then cooled to <80° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 equivalents) were added. The mixture was then heated to 121° C. again. 45.86 g (54.52 mL) of isophytol (150 mmol, 98% purity, 1 equivalent) was then added continuously to the reaction mixture (temperature of the reaction mixture: 120-125° C.) over a period of 2 hours, while the water formed during the reaction was removed by distillation. At 124-125 ℃ for 4 hours, overnight at room temperature, and after a further reaction time of another 2 hours at 125 ℃, the reaction mixture was cooled to room temperature and filtered through a glass suction filter D4 equipped with diatomaceous earth to remove catalyst 2. The filter cake was washed with 3*45mL n-octane and 3*45mL propylene carbonate. All mother liquors and washings were collected and combined. The phase of the eluent was separated. The propylene carbonate phase was extracted with 4*65mL n-octane. The n-octane phase combined was dried over sodium sulfate, and volatiles were removed under reduced pressure at 55 ℃ / 5 mbar plus 15 minutes oil pump vacuum: 64.58g crude α-tocopherol (93.1GC area % and 87.24GC weight %) in the form of a dark red clear viscous residue was obtained. This is equivalent to a yield of 87%. In addition, 172.31g of red clear propylene carbonate phase was obtained, which contained 93.6GC-area %, 6.2HPLC-weight % of unreacted TMH. This corresponds to a recovery of 93% TMH (70 mmol of 75 mmol TMH used in excess). 85.87 g of this propylene carbonate phase are recycled in 2.25.2.

[0512]

[0513] Example 2.25.2:

[0514] Preparation of fully racemic α-tocopherol:

[0515] 85.87 g of the propylene carbonate phase from 2.25.1 (containing 5.32 g, 34.96 mmol, 0.23 equivalents of TMH), 40.9 g (58.18 mL) of n-octane (plus 60 mL of octane in the dean-stark trap) and 0.22 g of catalyst 2 (dried overnight at 120° C., 50 mbar) / g of TMH (7.5 g of catalyst 2) were heated to a slight n-octane reflux (temperature of the reaction mixture: 120-123° C.) under a nitrogen stream and stirred at reflux for 15 minutes. The suspension was then cooled to <80° C. and 29.16 g (190.04 mmol) of trimethylhydroquinone (1.23 equivalents; total: 1.46 equivalents) were added. The mixture was then heated to 120° C. again. Then in the time period of 2 hours, 47.2g (56.12mL) of isophytol (154.4mmol, 97% purity, 1 equivalent) is continuously added to the reaction mixture (temperature of the reaction mixture: 120-125°C), while the water formed during the reaction is removed by distillation. After 4 hours at 124-125°C, overnight at room temperature, and further reaction time of another 2 hours at 125°C, the reaction mixture is cooled to room temperature and filtered to remove catalyst 2 by a glass suction filter D4 equipped with diatomaceous earth. The filter cake is washed with 3*45mL n-octane and 3*45mL propylene carbonate. Collect and combine all mother liquors and washings. The phase of the eluent is separated. The propylene carbonate phase is extracted with 4*65mL n-octane. The n-octane phases combined were dried over sodium sulfate and volatiles were removed under reduced pressure at 55°C / 5 mbar with an oil pump vacuum for 15 minutes: 65.70 g of crude α-tocopherol (92.9 GC area % and 87.71 GC weight %) in the form of a dark red clear viscous residue were obtained. This was equivalent to a yield of 87%. In addition, 172.31 g of red clear propylene carbonate phase was obtained, which contained 91.5 GC-area %, 5.5 HPLC weight % of unreacted TMH. This was equivalent to a recovery of >99% TMH (71 mmol in the 71 mmol TMH used in excess).

[0516]

Claims

1. A method for preparing a compound of formula I in R 1 , R 2 and R 3 are independently selected from hydrogen and methyl, R 4 Selected from C 1 -C 6 -alkyl, and X is selected from C 1 -C 20 -alkyl and C 2 -C 20 -alkenyl, The method The following steps are involved: a) providing a hydroquinone compound of formula II, Where R 1 , R 2 and R 3 As defined above, b) reacting the hydroquinone compound II provided in step a) with an unsaturated compound of the general formula III.a or III.b in the presence of a bentonite catalyst, in X is defined as above, Y is selected from OH, halogen, -OR 11 、-SR 12 and-SO 2 -R 12 , R 11 Selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkanoyl and trifluoroacetyl, and R 12 Selected from C 1 -C 6 -alkyl, trifluoromethyl and phenyl, wherein the phenyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from halogen and methyl, and c) reacting the condensation product obtained in step b) with C in the presence of a bentonite catalyst 2 -C 7 -carboxylic acid or with C 2 -C 7 -Carboxylic anhydride reaction; The bentonite catalyst used in step b) has a mass fraction of 100 to 600 m 2 / g of BET surface area, and having a residual acidity expressed in mg KOH / g bentonite determined by potentiometric titration of 5 to 50; as well as Wherein steps b) and c) are carried out in the presence of a polar aprotic solvent.

2. The process according to claim 1, wherein steps b) and c) are carried out in the presence of the same bentonite catalyst.

3. The process according to claim 1, wherein the bentonite catalyst used in steps b) and c) is subjected to an acid treatment before its use in steps b) and c).

4. The process according to claim 3, wherein the bentonite catalyst used in steps b) and c) is additionally subjected to a drying step before its use in steps b) and c).

5. The process according to any one of claims 1 to 4, wherein the bentonite catalyst has a mass of 150 to 400 m 2 / g of BET surface area.

6. The process according to any one of claims 1 to 4, wherein the bentonite catalyst has a residual acidity expressed as mgKOH / g bentonite, determined by potentiometric titration, of 10 to 40.

7. The process according to any one of claims 1 to 4, wherein the amount of free moisture in the bentonite catalyst is at most 25% by weight.

8. The process according to claim 7, wherein the amount of free moisture in the bentonite catalyst is at most 20 wt%.

9. The process according to any one of claims 1 to 4, wherein the weight ratio of the bentonite catalyst to the hydroquinone compound (II) used in step b) is from 0.1:1 to 1.5:

1.

10. The process according to any one of claims 1 to 4, wherein the bentonite catalyst used in steps b) and c) is separated from the reaction mixture after completion of the reaction in step c) and reused in the further reaction in step b).

11. The process according to any one of claims 1 to 4, wherein step c) is carried out in the polar aprotic solvent used in step b).

12. The process according to any one of claims 1 to 4, wherein the polar aprotic solvent is selected from at least one organic carbonate and a mixture consisting of at least one organic carbonate and at least one non-polar hydrocarbon compound.

13. The process according to any one of claims 1 to 4, wherein the reaction mixture obtained in step b) is directly used in the reaction in step c).

14. The method according to any one of claims 1 to 4, wherein the compounds of formula I and II R 1 , R 2 and R 3 Methyl and R 4 Selected from methyl.

15. The process according to any one of claims 1 to 4, wherein X is methyl or has one of the following meanings X-1 to X-6: Wherein * indicates the point of attachment to the chromane ring.

16. The method according to any one of claims 1 to 4, wherein in step a) the hydroquinone compound II is provided The following steps are involved: a.1) providing a quinone compound of formula IV, Where R 1 , R 2 and R 3 are independently hydrogen or methyl, a.2) catalytically hydrogenating the quinone compound of formula IV provided in step a.1) in the presence of hydrogen and a hydrogenation catalyst.

17. The method according to claim 16, wherein step a.2) is carried out in a carbonate solvent.

Images