RU2795497C2 - Synthesis of chromanol derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a process for the preparation of chromanol derivatives, more particularly to a process for the preparation of a compound of general formula I

where R¹, R² and R³ are independently selected from hydrogen and methyl, R⁴ is selected from hydrogen and C₁-C₆-alkanoyl and X is selected from C₁-C₂₀-alkyl and C₂-C₂₀- alkenyl. The proposed method includes stages a)–d). At stage a), a quinone compound of general formula II is provided

and at stage b) catalytic hydrogenation of a quinone compound of formula II is carried out in the presence of hydrogen, a hydrogenation catalyst and a carbonate solvent to obtain a hydroquinone compound of general formula III

/

Next, at stage c), the hydroquinone compound III is reacted with an unsaturated compound of the general formula IV.a or IV.b

where X is as defined above, Y is selected from OH, halogen, -OR¹¹, -SR¹² and -SO₂-R¹², R¹¹ is selected from C₁-C₄-alkyl, C₁-C₄-alkanoyl and trifluoroacetyl and R¹² is selected from C₁-C₆-alkyl, trifluoromethyl and phenyl, where phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 radicals selected from halogen and methyl, in the presence of a condensation catalyst, and at the stage d) if R⁴ is selected from C₁-C₆ alkanoyl, the condensation product obtained at Stage c) is reacted with a C₂-C₇ carboxylic acid or C₂-C₇ carboxylic acid anhydride in the presence of an esterification catalyst or reaction of the condensation product obtained at Stage c) with an activated C₂-C₇ carboxylic acid in the presence of a base.

EFFECT: providing a method for producing vitamin E derivatives, which is efficient and provides the desired products with high yield and selectivity without the need to use expensive, corrosive and/or environmentally harmful catalysts and solvents.

17 cl, 2 tbl, 37 ex

Description

The present invention relates to a process for the preparation of chromanol derivatives, in particular to a process for the preparation of compounds belonging to the vitamin E family.

Background of the Invention

Vitamin E is the most important fat-soluble antioxidant in biological systems. The term vitamin E includes all derivatives of tocol and tocotrienol with biological activity (2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydro -2H-chromen-6-ol (1.1), which is the most important vitamin E for 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).

Naturally occurring vitamin E encompasses the tocopherol compounds of formulas I.1 - I.4 (α-, β-, γ- and δ-tocopherol) as well as the tocotrienol compounds of formulas I.5 - I.8 (α-, β-, γ- and δ-tocotrienol).

These naturally occurring compounds exist in the form of individual isomers, ie. α-, β-, γ- and δ-tocopherols (I.1 - I.4) have the configuration 2R, 4R, 8R, and the corresponding α, β-, γ- and δ-tocotrienols (I.5 - I.8 ) are present as isomers 2R, 3E, 7E.

Industrially, α-tocopherol is mainly produced in the form of fully racemic α-tocopherol (all-rac-I.1) and all-rac-α-tocopherol acetate (all-rac I.1a), which are equimolar mixtures of all 8 possible stereoisomers. Generally, fully racemic α-tocopherol is synthesized by the condensation of trimethylhydroquinone (III.1) with fully racemic isophytol (fully racemic isophytol) as shown in Scheme 1. This condensation reaction involves the Friedel-Crafts alkylation of trimethylhydroquinone (III.1) followed by cycle closing reaction. The fully racemic α-tocopherol (all-rac-1.1) thus obtained is then converted to the more stable acetate form (all-rac-I.1a) by esterification with acetic anhydride.

Scheme 1: industrial synthesis of fully racemic α-tocopherol (acetate).

Other tocopherols, i.e. β-, γ- and δ-tocopherol, as well as the corresponding tocotrienols, in particular α-tocotrienol, are usually produced in a similar manner.

Over the past decades, a large number of methods for obtaining α-tocopherol have been developed. The key step in many of these methods is the Friedel-Crafts alkylation of the corresponding hydroquinone precursors, as shown in Scheme 1, which is carried out in the presence of a Friedel-Crafts catalyst.

Typically, strong Lewis acids such as zinc chloride, aluminum chloride, tin chloride, iron chloride, titanium tetrachloride, or boron trifluoroetherate, as well as combinations of strong Lewis acids and strong Bronsted acids, such as hydrochloric acid are used as catalysts for this Friedel-Crafts reaction. , sulfuric acid and phosphoric acid.

WO 9728151, for example, describes the reaction of 2,3,5-trimethylhydroquinone with isophytol to give α-tocopherol in the presence of cyclic carbonate solvents by using homogeneous Bronsted and Lewis acids such as orthoboric acid, oxalic acid, tartaric acid, citric acid or boron trifluoroetherate, at elevated reaction temperatures ranging from 145 to 155°C.

However, the use of these catalysts is associated with a number of disadvantages. First of all, they can promote the formation of by-products (for example, the use of oxalic acid, tartaric acid or citric acid usually increases the formation of unwanted phytadienes). In addition, these catalysts are generally not recoverable and reusable due to their instability with respect to water. In addition, the catalysts are used in stoichiometric quantities or with high catalytic loading. In addition, these catalysts are generally corrosive and wastes containing heavy metals such as zinc or tin and chlorides are often generated.

To overcome these disadvantages, heterogeneous catalysts have been used as a Friedel-Crafts alkylation catalyst.

In 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, for example, describes the use of zeolite catalysts such as Tseokar-10 or ASNC-ZP in the reaction of hydroquinones with tertiary isoprenoid allyl alcohols. The disadvantage of using zeolites is that the reactions must be carried out at high dilutions and that these zeolites are often not commercially available.

In 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 such as Amberlist 15 as a catalyst in the reaction of trimethylhydroquinone with isophytol. However, these catalysts usually have low catalytic activity and wastes containing heavy metals and chlorides are generated.

EP 677520 A1 and Matsui et al., Bull. Chem. soc. Japan, 1996, 69, 137 describe the use of ion-exchange bentonite, montmorillonite or saponite by treatment with scandium chloride or salts of other metals such as yttrium, lanthanum, etc. as a catalyst in the reaction of trimethylhydroquinone with isophytol, the disadvantage is that that a large amount of catalyst is required.

DE 2404621 describes a method for producing α-tocopherol by reacting trimethylhydroquinone with phytol, isophytol or a derivative thereof using a solid acid catalyst having a certain acid strength. Among others, naturally occurring minerals that exhibit acidity, such as acid clay, bentonite, kaolin or mordenite, are mentioned as suitable catalysts. In a specific example, bentonite is used as the catalyst, giving the desired α-tocopherol in 51.8% yield. Also here, large quantities of catalyst are required and the yields obtained are moderate.

2,3,5-Trimethylhydroquinone (III.1), which is commonly used as an aromatic structural unit in the industrial synthesis of all-racemic α-tocopherol, is usually prepared by reduction of 2,3,5-trimethylquinone (II.1) as shown in Scheme 2.

Scheme 2:

Many methods have been developed to reduce these quinones to the corresponding hydroquinones.

EP 0 264 823 B2, for example, describes a process for the preparation of 2,3,5-trimethylhydroquinone by catalytic hydrogenation of 2,3,5-trimethylquinone in the presence of a hydrogenation catalyst selected from platinum group metals supported on alkali metal-containing silicon oxide as a support. Suitable solvents for these catalytic hydrogenation reactions are aliphatic alcohols, aromatic alcohols, ketones, organic acids, organic acid esters, ethers, cyclic ethers, lactones and mixtures thereof.

The focus of the aforementioned developments is on identifying suitable reaction conditions that avoid environmentally harmful reagents and catalysts and simplify the reaction procedure, in particular, simplify the isolation of products. Thus, there is a constant search for new methods and new reagents, alternative to the already known ones.

The essence of the invention

Thus, it is an object of the present invention to provide a process for the preparation of vitamin E derivatives from the corresponding benzoquinone precursors, which is efficient and provides the desired products in high yield and selectivity without the need for expensive, corrosive and/or environmentally harmful catalysts and solvents. The method should be simple and laborious cleaning procedures should be avoided. In addition, the method must be applicable to large-scale production, and the catalyst used must be recyclable.

It has surprisingly been found that these and other objects are achieved by a process which comprises the catalytic hydrogenation of benzoquinone precursors to the corresponding hydroquinones in the presence of a carbonate solvent, followed by Friedel-Crafts alkylation of the hydroquinones thus obtained.

Accordingly, the present invention relates to a process for the preparation of a compound of general formula I

Where

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

R ⁴ is selected from hydrogen and C ₁ -C ₆ -alkanoyl, and

X is selected from C ₁ -C ₂₀ -alkyl and C ₂ -C ₂₀ -alkenyl,

Including the following stages:

a) providing a quinone compound of general formula II,

where R ¹ , R ² and R ³ have the meanings as defined above,

b) catalytically hydrogenating a quinone compound of formula II provided in step a) in the presence of hydrogen, a hydrogenation catalyst and in the presence of a carbonate solvent to obtain a hydroquinone compound of general formula III,

where R ¹ , R ² and R ³ have the meanings as defined above,

c) reacting the hydroquinone compound III provided in step b) with an unsaturated compound of general formula IV.a or IV.b

Where

X has a value as defined above,

Y is selected from OH, halogen, -OR ¹¹ , -SR ¹² and -SO ₂ -R ¹² ,

R ¹¹ is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkanoyl and trifluoroacetyl, and

R ¹² is selected from C ₁ -C ₆ -alkyl, trifluoromethyl and phenyl, where phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 radicals selected from halogen and methyl,

in the presence of a condensation catalyst, and

d) if R ⁴ is selected from C ₁ -C ₆ alkanoyl, reaction of the condensation product obtained in step c) with C ₂ -C ₇ carboxylic acid or C ₁ -C ₇ carboxylic acid anhydride in the presence of an esterification catalyst,

or reaction of the condensation product obtained in step c) with an activated C ₂ -C ₇ carboxylic acid in the presence of a base.

Detailed description of the present invention

In the context of the present invention, the term "alkyl", as used herein, refers to a linear or branched saturated hydrocarbon radical having from 1 to 3 ("C ₁ -C ₃ -alkyl"), from 1 to 4 ("C ₁ - C ₄ -alkyl"), from 1 to 6 ("C ₁ -C ₆ -alkyl") or from 1 to 20 ("C ₁ -C ₂₀ -alkyl") carbon atoms. C ₁ -C ₃ -Alkyl is methyl, ethyl, propyl and isopropyl. C ₁ -C ₄ -Alkyl is additionally n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C ₁ -C ₆ -Alkyl is also additionally, 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. C ₁ -C ₂₀ -Alkyl is also additionally, 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-trimethydridecyl, octadecyl, isooctadecyl and the like.

In the context of the present invention, the term "C ₁ -C ₄ -alkanoyl" means a C ₁ -C ₄ -alkyl group, as defined above, attached through a carbonyl [(C=O)] group to the rest of the molecule. The term "C ₁ -C ₆ alkanoyl" means a C ₁ -C ₆ alkyl group, as defined above, attached via a carbonyl [(C=O)] group to the rest of the molecule. C ₁ -C ₄ -alkanoyl is methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butyl carbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl or 1,1-dimethylethylcarbonyl. C ₁ -C ₆ -alkanoyl is additionally, for example, n-pentylcarbonyl, 1-methylbutylcarbonyl, 2-methylbutylcarbonyl, 3-methylbutylcarbonyl, 1,2-dimethylpropylcarbonyl, n-hexylcarbonyl, 1-methylpentylcarbonyl, 2-methylpentylcarbonyl, 3 -methylpentyl carbonyl, 4-methylpentyl carbonyl or 1,3-dimethylbutylcarbonyl.

The term "halogen" means in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine. The halogen substituent on phenyl is preferably Cl or Br.

The compounds obtained by the method according to the present invention are compounds of general formula I

Where

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

R ⁴ is selected from hydrogen, C ₁ -C ₆ alkanoyl, and

X is selected from C ₁ -C ₂₀ alkyl and C ₂ -C ₂₀ alkenyl.

Due to their structure, the compounds (I) can be present in the form of pure enantiomers or diastereomers, as well as in the form of mixtures of enantiomers or diastereomers.

The term "stereoisomers" embraces optical isomers such as enantiomers or diastereoisomers, the latter being due to more than one stereogenic center in the molecule. Compounds of formula (I) where X is not methyl have at least one stereogenic center, namely the carbon atom in position 2 of the chroman ring. In addition, in the compounds (I) the radical X may also have at least one stereogenic center, for example if X is selected from 4,8-dimethylnonyl or 4,8,12-trimethyltridecyl. The present invention relates both to pure enantiomers or diastereoisomers of compounds (I) and mixtures thereof.

In addition, if the radical X is selected from C ₂ -C ₂₀ -alkenyl, the compounds (I) may also have at least one double bond, which may have the E or Z configuration, for example, if X represents isoprenyl fragments 4, 8-dimethyl-3,7-nonadienyl or 4,8,12-trimethyl-3,7,11-tridecatrienyl. Thus, the present invention also relates to compounds (I) in which the double bond(s), if present, has/have a pure E or Z configuration and/or is/are present as an E/Z mixture(s) .

Preferably, in the compounds (I) and (III) of the method according to the present invention, the radicals R ¹ , R ² and R ³ have the following meanings:

R ¹ is methyl,

R ² is methyl, and

R ³ is methyl,

or

R ¹ is methyl,

R ² is hydrogen, and

R ³ is methyl,

or

R ¹ is hydrogen,

R ² is methyl and

R ³ is methyl,

or

R ¹ is hydrogen,

R ² is hydrogen, and

R ³ is methyl.

In particular, in compounds (I) and (III) the radicals R ¹ , R ² and R ³ are methyl.

Preferably, in the compounds (I) of the method according to the present invention, the R ⁴ radical is selected from hydrogen and C ₁ -C ₄ -alkanoyl, more preferably from hydrogen or C ₁ -C ₂ -alkanoyl, in particular from hydrogen and ethanoyl.

Preferably, in the compounds (I), (IV.a) and (IV.b) of the method according to the present invention, the fragment X is selected from methyl or has one of the following values X-1 - X-6

where * indicates the point of attachment to the chroman ring.

Specifically, in the compounds (I), (IV.a) and (IV.b) according to this first embodiment, the moiety X is selected from (X-3) or (X-6)

where * indicates the point of attachment to the rest of the molecule.

According to a preferred embodiment, in compounds (I)

R ¹ is methyl,

R is methyl, and

R ³ is methyl,

or

R ¹ is methyl,

R ² is hydrogen, and

R ³ is methyl,

or

R ¹ is hydrogen,

R ² is methyl and

R ³ is methyl,

or

R ¹ is hydrogen,

R is hydrogen, and

R ³ is methyl,

R ⁴ is selected from hydrogen and C ₁ -C ₄ -alkanoyl, and

X is selected from methyl or a radical of formulas X-1 to X-6.

According to a more preferred embodiment, in compounds (I)

R ¹ is methyl,

R ² is methyl, and

R ³ is methyl,

or

R ¹ is methyl,

R is hydrogen, and

R is methyl,

or

R ¹ is hydrogen,

R is methyl, and

R ³ is methyl,

or

R ¹ is hydrogen,

R ² is hydrogen, and

R ³ is methyl,

R ⁴ is selected from hydrogen and C ₁ -C ₂ -alkanoyl, in particular from hydrogen and ethanol, and

X is methyl or one of the following (X-3) or (X-6)

where * indicates the point of attachment to the rest of the molecule.

According to a specific embodiment in the compounds (I)

R ¹ , R ² and R ³ are methyl,

R ⁴ is selected from hydrogen and ethanol, and

X has one of the following values (X-3) or (X-6)

where * indicates the point of attachment to the rest of the molecule.

Preferably, in compounds (IV.a) and (IV.b), the radical Y is selected from OH, Cl, Br, I, OR ¹¹ , -SR ¹² and -SO ₂ -R ¹² , where

R ¹¹ is selected from C ₁ -C ₄ alkanoyl and trifluoroacetyl, and

R ¹² is selected from C ₁ -C ₃ alkyl, trifluoromethyl, phenyl, 4-methylphenyl and pentafluorophenyl.

More preferably, in compounds (IV.a) and (IV.b), the radical Y is selected from OH, Br, OR ¹¹ , -SR ¹² and -SO ₂ -R ¹² where

R ¹¹ is selected from acetyl and trifluoroacetyl, and

R ¹² is selected from methyl, trifluoromethyl and 4-methylphenyl.

In particular, in compounds (IV.a) and (IV.b), the radical Y is selected from OH, OR ¹¹ and -SO ₂ -R ¹² where

R ¹¹ is selected from acetyl, and

R ¹² is selected from methyl, trifluoromethyl and 4-methylphenyl.

Stage a):

Step a) according to the present invention comprises providing a quinone compound of general formula (II).

These quinone compounds are either chemically available or can be prepared from readily available precursors by methods known in the art.

For example, 2,3,5-trimethylquinone can be obtained by catalytic methylation of m-cresol to 2,3,6-trimethylphenol (step i) followed by oxidation of the 2,3,6-trimethylphenol thus obtained using an oxidizing agent (step ii)) as shown in diagram 3.

Scheme 3:

The catalytic methylation in step i) is usually carried out with methanol or dimethyl ether as the alkylating agent in the presence of a metal oxide catalyst such as, for example, alumina, silicon oxide, magnesium oxide, calcium oxide, barium oxide, iron oxide, oxide chromium, zinc oxide, manganese oxide, zirconium oxide, thorium oxide, etc., as well as catalysts based on mixed metal oxides.

Individual reaction conditions for the catalytic methylation of phenols such as m-cresol are well known to those skilled in the art.

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

Suitable oxidizing agents are, for example:

- hydrogen peroxide, oxygen or an oxygen-containing gas in the presence of catalytic amounts of metal salts, such as Mg (II) -, Ca (II) -, Ba (II) -, Cu (II) -, Fe (II) -, Cr (II ) -, Mn (II) -, Co (II) -, Ni (II) -, Zn (II) -, sulfates or chlorides, as well as mixtures of these metal salts or a catalyst based on a noble metal, such as, for example, ruthenium , rhodium, platinum or palladium catalyst;

- mineral acids such as nitric acid, sulfuric acid, perchloric acid, hypochlorous acid, perchloric acid, iodic acid or periodic acid; or

- organic peroxyacids such as perbenzoic acid or meta-chloroperbenzoic acid.

Suitable reaction conditions for this oxidation reaction are well known to those skilled in the art.

Stage b):

Step b) according to the present invention comprises the catalytic hydrogenation of a quinone compound of formula II provided in step a), in the presence of hydrogen, a hydrogenation catalyst and in the presence of a carbonate solvent, to obtain a hydroquinone compound of general formula III,

where R ¹ , R ² and R ³ have the meanings as defined above.

In step b), the benzoquinone (II) is usually dissolved in a carbonate solvent and brought into contact with hydrogen and a hydrogenation catalyst.

Hydrogenation catalysts that can be used in the catalytic hydrogenation in step b) are those commonly used in the art for catalyzing the hydrogenation of organic compounds. Some examples of these include palladium chloride on activated carbon, activated nickel, nickel-nickel oxide, platinum-platinum oxide, platinum black, platinum on activated carbon, copper chromite, Raney nickel, palladium, palladium black, palladium on activated carbon, palladium alloy , nickel, copper impregnated alumina, activated alumina, Raney copper, chromium, vanadium, molybdenum, etc.

Preferably, the hydrogenation catalyst used in step b) is a heterogeneous hydrogenation catalyst, more preferably supported on a metal catalyst.

Suitable carriers are, for example, carbon, carbon black, activated carbon, graphite, alumina, 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.

Even more preferably, the hydrogenation catalyst used in step b) is a carbon-supported catalyst.

Specifically, the hydrogenation catalyst used in step b) is a carbon-supported noble metal catalyst, that is, a noble metal catalyst containing a carbon-based support material (C), such as activated carbon.

In principle, suitable carbon-based support materials are all carbon materials known to those skilled in the art for such applications. Suitable carbon-based carrier materials include, for example, carbon, carbon black, activated carbon and graphite. The carrier materials can be used in the form of shaped bodies, granules, threads, pellets, chips, tablets or pieces. The BET surface area of the carrier materials (25° C.) is typically in the range of 1 to 10,000, preferably 10 to 5,000 m ² /g, but in most cases is not critical for the method of the present invention.

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

In particular, the hydrogenation catalyst used in step b) is selected from a carbon-supported Pd catalyst, namely Pd on activated carbon.

The metal content of the supported metal catalyst used in step b) according to the present invention is typically between 0.1% and 20% by weight. %, preferably in the range from 1% to 15 wt. %, based on the total weight of the noble metal catalyst supported on carbon.

Typically, the amount of hydrogenation catalyst used in stage b) according to the present invention is from 0.05% to 20 wt. %, preferably in the range from 0.1% to 10 wt. %, more preferably in the range from 0.2% to 5 wt. %, based on the amount of quinone present in the reaction mixture.

Catalytic hydrogenation can be carried out at atmospheric pressure or at elevated pressure. Higher pressures generally result in higher hydrogenation rates. Extremely high pressure is not required because benzoquinones are easily reduced. The catalytic hydrogenation in step b) is usually carried out at a pressure in the range from 1 to 100 bar, preferably in the range from 1 to 50 bar, especially in the range from 2 to 30 bar.

The hydrogenation is carried out at a temperature high enough to promote the reduction of benzoquinone, but not so high as to cause decomposition of the reactants, reaction medium or products. A suitable reaction temperature is usually 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.

According to the present invention, the catalytic hydrogenation reaction in step b) is carried out in the presence of a carbonate solvent selected from organic carbonates.

Preferably, the carbonate solvent is selected from cyclic or linear carbonates of general formulas VI.a and VI.b

Where

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

R ¹⁸ is selected from hydrogen, phenyl and C ₁ -C ₅₁ -alkyl, where C ₁ -C ₁₅ -alkyl is unsubstituted or substituted with 1, 2, or 3 radicals selected from C ₁ -C ₃ -alkoxy, polyalkylene oxide, phenyl and phenoxy, in particular from hydrogen, phenyl, C ₁ -C ₃ -alkyl and benzyl, and

R ¹⁹ are independently selected from C ₁ -C ₄ -alkyl, in particular from ethyl and n-propyl.

More preferably, the carbonate solvent is selected from cyclic or linear carbonates of general formulas VI.a and VI.b

Where

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

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

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

Among these carbonate solvents, those carbonate solvents are preferred which have a boiling point of at least 100°C, more preferably at least 120°C, in particular at least 140°C.

In particular, 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.

These cyclic and acyclic carbonates do not cause any toxicological problems, which is very important for the preparation of compounds of the general formulas I and II. In addition, these solvents are highly biodegradable.

The reaction in step b) can optionally be carried out in the presence of an apolar hydrocarbon solvent (HS).

Accordingly, according to an alternative embodiment of the present invention, step b) is carried out in a solvent mixture consisting of at least one carbonate solvent as defined above and at least one apolar hydrocarbon solvent (HS).

Preferably, the apolar hydrocarbon solvent (HS), if present, is selected from the following groups:

HS.1 linear and branched alkanes having from 5 to 15 carbon atoms, such as pentane, hexanes, heptnanes, octanes, nonanes, decanes, naphtha and petroleum ether;

HS.2 cycloalkanes having from 5 to 10 carbon atoms, such as cyclohexane;

HS.3 aromatic hydrocarbons having from 6 to 12 carbon atoms, such as benzene, toluene, xylenes, ethylbenzene and tetralin;

and their mixtures.

More preferably, the apolar hydrocarbon solvent (HS) is selected from the groups HS.1 and HS.2.

In particular, the apolar hydrocarbon solvent (HS) is selected from hexane, cyclohexane, heptane, octane and nonane, more specifically from heptane and octane.

According to this alternative embodiment, the content of carbonate solvent in this mixture of solvents is usually from 35 to 99 wt. %, preferably in the range from 50 to 99 wt. %, in particular in the range from 50 to 90 wt. %, based on the total weight of the solvent mixture.

Accordingly, the weight ratio of carbonate solvent and HS used in step b) is usually in the range from 1:3 to 100:1, preferably in the range from 1:1 to 100:1, in particular in the range from 1:1 to 10:1.

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

According to this alternative embodiment, solvent mixtures consisting of at least one carbonate solvent and at least one apolar hydrocarbon solvent of the HS group are preferred. 1.

Specifically, according to this alternative embodiment, the solvent mixture consists of at least one carbonate solvent 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 apolar hydrocarbon solvent (HS) selected from heptane and octane.

According to a particular embodiment of the present invention, step b) is carried out in at least one carbonate solvent (PS) as defined above.

Catalytic hydrogenation can be carried out in various reactors known for this purpose, such as a series loop reactor, 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 in particular, trickle-bed reactors.

The reaction product, ie the compound of formula (III) obtained in step b), is usually worked up by filtering off the hydrogenation catalyst. The reaction mixture thus obtained can be used directly in step c) of the process according to the present invention.

If desired, the reaction mixture thus obtained can be further processed in the usual manner, for example by mixing with water, phase separation and, if necessary, purification of the crude products by chromatographic methods, distillation or recrystallization.

According to a preferred embodiment according to the present invention, the reaction mixture obtained in step b) is used directly in the reaction in step c) of the process according to the present invention, after removal of the hydrogenation catalyst.

Stage c):

Step c) according to the present invention comprises reacting the compound (III) provided in step b) with an unsaturated compound of general formula (IV.a) or (IV.b)

Where

X has one of the values above,

Y is selected from OH, halogen, -OR ¹¹ , -SR ¹² and -SO ₂ -R ¹² ,

R ¹¹ is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkanoyl and trifluoroacetyl, and

R ¹² is selected from C ₁ -C ₆ -alkyl, trifluoromethyl and phenyl, where phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 radicals selected from halogen and methyl,

in the presence of a condensation catalyst.

In general, any condensation catalysts which are capable of catalyzing Friedel-Crafts alkylations and/or (intramolecular) olefin hydroxalkylations (intramolecular cyclization reaction) can be used in step c) of the process of the present invention.

Suitable conventional condensation catalysts are, for example, Lewis acids such as zinc chloride, aluminum chloride, tin chloride, iron chloride, titanium tetrachloride or boron trifluoroetherate, Bronsted acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and acid heterogeneous catalysts, as well as their combinations.

According to a preferred embodiment of the present invention, the condensation catalyst used in step c) is selected from an acidic heterogeneous catalyst.

Suitable acid heterogeneous catalysts are selected, for example, from cation exchange resins, for example cation exchange resins containing sulfonic acid groups such as Amberlist 15 or Dowex 50W, zeolites such as H-BFA zeolites, H-Y zeolites, pentasil type zeolites, Tseokar-10 zeolites or K-10; as well as naturally occurring minerals having a certain acidity, such as acid clay, montmorillonite, bentonites, kaolin, saponites or mordenites.

The preferred condensation catalyst used in step c) according to the present invention is selected from silicate clay minerals containing the elements H, C, O, Si, Al, Mg, Ca, Li, Na, K, Fe, Zn, S, F and all their combinations. Preferred silicate minerals that can be used as a condensation catalyst in step c) of the present invention include, for example, pyrophyllite, talc, micas (e.g. muscovite, paragonite, phlogopite, biotite, lepidolite, zinnwaldite, taeniolite, fluoro-tetrasilicate mica) , brittle micas (margarite, chloritoid, zeiberite, clintonite), aqueous micas, illites, chlorites, vermiculites, smectites (montmorillonite, saponite, nontronite, beidellite, sauconite, hectorite, fluorohectorite), candites, serpentines and/or palygorskites (attapulgite, sepiolite )

More preferably, the condensation catalyst used in step c) of the present invention is selected from silicate clay minerals containing montmorillonites as described, for example, in Klockmann's textbook of mineralogy, 16th edition, F. Euke Verlag 1978, pages 739-765 and in R.M. Barrer Zeolites and Clay Minerals as Sorbents and Molecular Sieves, Academic Press, and in Y. Izumi, K. Urabe, M. Onaka Zeolite, Clay, and Heteropoly Acid in Organic Reactions, VCH.

Depending on their catalytic properties in their natural or manufactured form, these heterogeneous condensation catalysts can be used in raw form or they can be processed before use to change their catalytic properties. In this respect, the expression "processed" refers to chemical processing. Typically, chemical treatment of heterogeneous condensation catalysts includes acid treatment, alkaline treatment, metal salt treatment (cation exchange), or organic treatment. Preferably, the chemical treatment of the heterogeneous condensation catalyst comprises treatment with metal salts (cation exchange) or acid treatment. The acid treatment of the heterogeneous condensation catalyst is usually carried out with strong Bronsted acids and/or Lewis acids.

According to an even more preferred embodiment of the present invention, the reaction of step c) is carried out in the presence of a treated bentonite catalyst.

Bentonite is formed from highly colloidal and plastic clay. Bentonite is often used as a thickener and filler for paints, as an additive for ceramics, and for health products (such as cosmetics, foods, or pharmaceuticals). Bentonites are good adsorbents and are characterized by high cation exchange capacity, strong swelling ability and low permeability.

Typically, the main component of bentonite is montmorillonite, a clay mineral of the smectite group. Montmorillonite consists of two layers of silicon tetrahedra with a central layer of one aluminum octahedron between them. It has hydroxyl groups between the layers as well as on the surface.

In principle, all deposits containing montmorillonite, such as those listed in the monograph "The Economics of Bentonite", 8th Edition 1997, Roskill Information Services Ltd, London, can be considered as suitable sources of bentonites. Depending on their origin, bentonites may contain, in addition to montmorillonite, varying amounts of various associated minerals, as defined above, and non-mineral components. Such associated minerals and non-mineral components are, in particular, quartz, feldspar, kaolin, muscovite, zeolites, titanium oxides, iron oxides, illites, mica calcite and/or gypsum. The preferred raw material is a raw material with a high content of montmorillonite and, accordingly, a low content of secondary components, since the amount of pure montmorillonite in bentonite determines its characteristics. The higher the content of montmorillonite in bentonite, the better its performance as an industrial raw material. The content of montmorillonite can be determined, for example, by the adsorption of methylene blue.

Preferred starting materials have a methylene blue value of at least 250 mg/g, preferably at least 290 mg/g, in particular at least 320 mg/g. A particularly preferred feedstock is one in which the exchangeable cations consist of a high percentage of alkali metals, in particular sodium. With regard to charge equivalents, these starting materials contain at least 25%, preferably at least 40% of monovalent exchangeable cations. This sodium bentonite raw material is found in nature, known sources of sodium containing bentonites are in Wyoming/USA or India, for example, they are also known by their origin as "Western bentonites", "Wyoming bentonites" or by their properties as " swelling bentonites. Bentonites with a high content of alkaline earth cations, especially calcium, are known as "subbentonites" or "southern bentonites" and can be converted to sodium-containing bentonites by alkaline activation.

Finally, it is also possible in principle to produce suitable synthetic clay minerals, for example by adding organic cations or complex metal cations (PILC) and use them in the present invention (M. M. Herling et al. Z. Anorg. Allg. Chem. 2014, 640, 3-4.547-560 G. Poncelet and JJ Fripiat Handbook of Heterogeneous Catalysis ( ^2nd Edition) 2008, 1, 219-247).

Clay minerals of natural origin may, in addition to mineral impurities, also contain non-mineral impurities, especially carbon compounds. The preferred raw materials are bentonites with a total carbon content of less than 3 wt. %, preferably less than 1 wt. %, particularly preferably less than 0.5 wt. %.

It is well known that the macroscopic properties and applicability of bentonites are closely related to the quantity and quality of the montmorillonite they contain, their pH value (residual acidity), particle size and their porous microstructure (eg surface area, porosity).

Bentonites can be divided into natural bentonites, i.e. untreated bentonites, and processed bentonites (see, for example, J. Nones et al., Applied Clay Science, 2015, 105-106, 225-230). According to a preferred embodiment of the present invention, the reaction in step c) is carried out in the presence of a treated bentonite catalyst.

The term "treated bentonite" as used herein refers to bentonites where the structure, texture and other properties of the bentonite have been modified by chemical treatment and/or heat treatment. Thus, as used herein, the term "treated bentonite" refers to chemically treated and/or thermally treated bentonite. Typically, the chemical treatment of bentonites includes acid, alkali or organic treatment. Bentonites obtained by treatment with acid or alkali are also called "activated bentonites" (acid-activated bentonites or alkali-activated bentonites).

The term "acid-treated bentonite" or "acid-activated bentonites" in the context of the present invention refers to bentonites that are treated with Bronsted acid, for example a mineral acid such as HCl or H ₂ SO ₄ , H ₃ PO ₃ , HNO ₃ boric acid, silicic acid, carboxylic acids, such as formic acid or acetic acid, or other organic acids such as trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid or trifluoromethanesulfonic acid. Preference is given to HCl and/or H ₂ SO ₄ or mixtures of HCl and/or H ₂ SO ₄ with other inorganic or organic acids. Typically, acid-activated bentonites are widely used as bleaching earth for decolorizing oils.

Mineral acid treatment is also known to impart surface acidity to the clay, which improves its catalytic properties (P. Komandel, Applied Clay Science, 2016, 131, 84-99; DA D'Amico et al. Applied Clay Science, 2014, 99, 254 -260). Without wishing to be bound by a particular theory, it is believed that during acid treatment or acid activation, respectively, the edges of the silicate sheets of clay minerals in bentonite open and the Al ³⁺ and Mg ²⁺ cations of the octahedral sheet become soluble. The chemistry of this activation process, where an acidic hydrogen ion, eg an acidic hydrogen ion from sulfuric acid, opens the lamellar structure of clay minerals in bentonite and forms acid sites, eg, is illustrated in J. Amorim et al. Hydrocarbon Engineering 2016, 21, 11, 83-8. The final acid-treated bentonites contain amorphous, porous, protonated and hydrated silica with a three-dimensional cross-linked structure (P. Komandel Applied Clay Science, 2016, 131, 84-99).

Methods for preparing acid-activated clay minerals, in particular layered silicates such as bentonites, are well known in the art; a review is presented, for example, in EP0398636 (B1), and a detailed method for the acid activation of clay minerals such as bentonites can be found, for example, in DE10245198 (A1).

Alkaline treatment of bentonites refers to the treatment of bentonites with mineral bases such as NaOH, KOH or sodium carbonate, or organic bases such as ammonia, trimethylamine or tetraalkylammonium hydroxides. Alkaline activation is usually carried out by treatment with sodium carbonate.

Organic treatment of bentonites refers to the treatment of bentonites with organic compounds such as quaternary ammonium cations (eg alkylammonium and α-ω-dialkylammonium).

Other organic and inorganic compounds that are exchanged with the above minerals include: hydrazine, urea, formamide, acetamide, Li, Na, K, Rb, Cs and _NH4 lower fatty acid salts (acetates, propionates, cyanoacetates), oxalates, glycolate , alaninate, lysinate, lactate, glycerin, acetylacetone, α-methoxyacetylacetone, acetoacetic acid ethyl ester, nonantrione-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 diglycide ether, triethylene glycol, diethylene glycol, triethylene glycol diacetate, diethylene glycol diacetate, hexanediol-1:6, pentanediol -1:5, 2:4-hexadiindiol-1:6.

Other organic bases which are exchanged with the above 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, otoluidine.

Other long chain alkylammonium salts which are exchanged in the minerals described above are 1-n-alkylpyridinium bromides and cetyltrimethylammonium bromide.

In addition, glycine and its peptides, a variety of other amino acids and ligands that are exchanged with the minerals described above, are described in R.M. Barrer Zeolites and Clay Minerals as Sorbents and Molecular Sieves, Academic Press, and references cited herein.

Typically, the "treated bentonite catalyst" is selected from acid-treated bentonites, that is, bentonites treated with Bronsted acids. Preferably, the "treated bentonite catalyst" is selected from bentonites treated with mineral acids as well as bentonites treated with strong organic acids. In particular, the "treated bentonite catalyst" is selected from bentonites treated with mineral acids.

These bentonite-based catalysts do not cause corrosion problems for the reaction apparatus or contamination of wastewater with metal ions or inorganic acids, and are acidic enough to carry out the reaction in step c) at reasonable to high reaction rates.

Acid-treated bentonites are either commercially available or can be prepared using methods that are well described in the art, as shown above.

Commercially available acid-treated bentonites (for example, also known as acid-leached bentonites having CAS number 70131-50-9) that can be used as catalysts in the reaction of step c) are, for example:

montmorillonite K 10, montmorillonite K 30, montmorillonite (aluminum cross-linked clay) (CAS 139264-88-3), montmorillonite-KSF (CAS 1318-93-0), available from Sigma-Aldrich, for example;

- TONSIL™ catalysts from Clariant Produkte (Deutschland) GmbH.

Generally, the treated bentonite catalyst has a BET surface area in the range of 50 to 800 ^m2 /g, preferably in the range of 100 to 600 ^m2 /g, more preferably in the range of 120 to 500 ^m2 /g, in in particular in the range from 150 to 400 m ² /g. The expression "BET surface area" as used herein refers to the well known Brunauer-Emmett-Teller method of determining surface area. The BET surface area values given in this application are determined by nitrogen adsorption according to the BET method essentially in accordance with DIN 66131 (1973), as detailed below.

Generally, the treated bentonite catalyst has a residual acidity, measured in mg KOH/g bentonite by titration with potentiometric indication, 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 ranging from 15 to 40. Residual acidity (mg KOH/g bentonite) is determined using the following standard procedures as described in the experimental section below.

Briefly, the determination of the residual acidity of the treated bentonite catalyst is carried out by first preparing an aqueous slurry with a certain amount of bentonite catalyst. An aqueous solution of NaOH at a certain concentration is then titrated into this aqueous bentonite slurry until the pH of the bentonite slurry is in the alkaline range (pH>7.0), which corresponds to the end point of the titration. The pH value is determined potentiometrically using a pre-calibrated KCl-pH electrode (potentiometric indication). The amount of NaOH required to reach the endpoint of the titration is then calculated (in milligrams) per gram of catalyst added to the aqueous slurry. This calculated value corresponds to the residual acidity in mg KOH/g bentonite.

Usually the amount of free moisture in the catalyst based on the treated bentonite is at most 30 wt. %, preferably at most 25 wt. %, preferably at most 20 wt. %.

The amount of free moisture in the treated bentonite is determined by weighing an individual bentonite against an anhydrous sample of the same bentonite. An anhydrous sample is obtained by drying in a vacuum oven at a temperature of 100 to 200°C, optionally under a reduced pressure below 200 mbar, preferably at a temperature in the range from 100 to 150°C and under a reduced pressure below 10 mbar, in particular below 1 mbar, to constant weight.

According to this more preferred embodiment, the amount of treated bentonite catalyst used in step c) of the process according to the present invention is in the range of 1 to 750 g per mole of unsaturated alkanol of general formula IV.a or IV.b used in step c) . Preferably, the amount of treated bentonite catalyst used in step c) is in the range of 5 to 500 g per mole of compound IV.a or IV.b., more preferably in the range of 10 to 250 g per mole of compound IV.a or IV.b., even more preferably in the range of 15 to 200 g per mol of compound IV.a or IV.b, in particular in the range of 20 to 150 g per mol of compound IV.a or IV.b used in the step With).

Generally, the weight ratio of the treated bentonite catalyst and compound (III) used in step c) is in the range of 0.01:1 to 2.5:1, preferably in the range of 0.03:1 to 1, 3:1, more preferably in the range from 0.04:1 to 1:1, in particular in the range from 0.05:1 to 0.7:1.

The porous structure of bentonite can be further modified by hydration and dehydration techniques, as is the case with thermal activation, for example (L.A. Shah et al. Applied Clay Science, 2018, 162, 155-164).

According to a particular embodiment of the present invention, the treated bentonite catalyst is subjected to a drying step prior to its use in step c).

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

The drying step can generally be carried out at atmospheric pressure or under reduced pressure. Preferably, the drying step is carried out under reduced pressure. In particular, the drying step is carried out at a pressure in the range from 0.1 to 500 mbar, more specifically in the range from 1 to 200 mbar.

The drying time of the treated bentonite catalyst depends on the temperature and pressure used in the drying step and thus can vary over a wide range. Typically, the drying time of the treated bentonite catalyst is from several minutes to several days, but preferably is in the range of 30 minutes to 2 days.

The reaction in step c) is usually carried out at a temperature in the range from 50 to 200°C, preferably in the range from 70 to 170°C, in particular in the range from 80 to 150°C.

The reaction in step c) can generally be carried out at atmospheric pressure or at elevated or reduced pressure.

The reaction in step c) can take place in the absence or presence of an inert gas. The expression "inert gas" as used herein generally means a gas that, under the prevailing reaction conditions, does not enter into any reactions with the starting materials, reagents or solvents involved in the reaction, or with the resulting products. Preferably, the reaction in step c) 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.

The reaction in step c) is usually carried out in an organic solvent. Preferably, the solvent used in step c) of the present invention is selected from at least one polar aprotic solvent (PS) as well as solvent mixtures consisting of at least one polar aprotic solvent (PS) and at least one apolar hydrocarbon solvent (HS) as defined above.

Suitable polar aprotic solvents (PS) are, for example, selected from the following groups:

PS.1 organic carbonates, i.e. linear and cyclic carbonates, such as 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;

PS.2 ketones, such as diethyl ketone (102°C) or methyl isobutyl ketone (116°C);

PS.3 lactones, such as γ-butyrolactone (204-206°C);

PS.4 lactams, such as N-methyl-2-pyrrolidone (NMP, 203° C.);

PS.5 nitriles, such as acetonitrile (82°C) and valeronitrile (117°C);

PS.6 nitro compounds, such as nitromethane (101°C);

PS.7 tertiary carboxamides, such as dimethylformamide (153°C);

PS.8 urea derivatives such as tetramethylurea (177°C) and dimethylpropyleneurea (DMPU, 247°C);

PS.9 sulfoxides, such as dimethyl sulfoxide (DMSO, 189°C);

PS. 10 sulfones, such as sulfolane (285°C)

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

PS.12 glycol ethers such as alkylene glycol dialkyl ethers, dialkylene glycol dialkyl ethers and polyalkylene glycol dialkyl ethers;

and their mixtures.

Among these groups, those polar aprotic solvents (PS) are preferred which have a boiling point of at least 100°C, more preferably at least 120°C, in particular at least 140°C.

More preferably the polar aprotic solvent (PS) is selected from the groups PS.1, PS.3, PS.4, PS.7, PS.8, PS.9, PS.10 and PS.12, even more preferably from PS.1 , PS.7, PS.8 and PS.12, even more preferably from PS.1 and PS.12, in particular H3PS.1.

In particular, the polar aprotic solvent (PS) is selected from cyclic or linear carbonates of general formulas VIa and VI.b as defined above.

Preferably, the apolar hydrocarbon solvent (HS) is selected from the groups HS.1 and HS.2.

More preferably, the apolar hydrocarbon solvent (HS) is selected from hexane, cyclohexane, heptane, octane and nonane, more specifically from heptane and octane.

According to a preferred embodiment according to the present invention, step c) is carried out in a solvent mixture consisting of at least one polar aprotic solvent (PS) as defined above and at least one apolar hydrocarbon solvent (HS) as defined above.

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

Accordingly, the weight ratio of PS and HS used in step c) is generally in the range from 1:3 to 100:1, preferably in the range from 1:1 to 100:1, in particular in the range from 1:1 up to 10:1.

According to this preferred embodiment, polar aprotic solvents (PS) are preferred which are immiscible or only moderately miscible with at least one apolar hydrocarbon solvent (HS), which means that step c) is carried out in a two-phase solvent mixture consisting of a PS-phase and HS phases. In this regard, the term "moderately miscible" means that less than 5 wt. %, preferably less than 2 wt. %, more preferably less than 1 wt. %, in particular less than 0.5 wt. % polar aprotic solvent (PS) is present in the HS phase.

According to this preferred embodiment, solvent mixtures consisting of at least one polar aprotic solvent of the group PS.1 and at least one apolar hydrocarbon solvent of the group HS.1 are preferred.

In particular, according to 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 apolar hydrocarbon solvent (HS) selected from heptane and octane.

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

The compounds of general formula (III) used in step c) are readily soluble in the polar aprotic solvent (PS-phase), while the apolar reaction product obtained in step c), i.e. the alkylation or condensation product, which is usually separated from the polar aprotic solvent after cooling the reaction mixture, we will dissolve well in apolar hydrocarbon solvent (HS-phase). Thus, the use of the above solvent mixtures has the advantage that the reaction mixture obtained in step c) can be easily separated by phase separation into a PS phase containing most or substantially all of the unreacted compound (III) as well as the condensation catalyst, and an HS phase containing most or substantially all of the apolar reaction product obtained in step c). If necessary, the separation of the apolar reaction product obtained in step c) from the PS phase can be completed by extraction with an apolar hydrocarbon solvent (HS). The separated PS phase can then be returned to the reaction in step c) or reused later in another reaction in step c). The separated HS phase can be directly subjected to the next process step or purification step. In addition, the water generated during the reaction in step c) can be easily distilled off from the PS phase, allowing the polar aprotic solvent (PS) to be easily recycled. In addition, the use of an apolar hydrocarbon solvent (HS) makes it possible to effectively remove by distillation the water formed during the reaction in step c) through the formation of an azeotropic mixture.

According to a particularly preferred embodiment of the present invention, step c) is carried out in the same carbonate solvent or in the same carbonate solvent/apolar hydrocarbon solvent mixture as used in step b).

The concentration of compound (III) in a polar organic solvent (PS) is usually in the range from 2 to 50 wt. %, preferably in the range from 3 to 45 wt. %, in particular in the range from 5 to 40 wt. %.

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

Compounds of general formulas IV.a and IV.b are either commercially available or can be obtained from readily available precursors by methods known in the art, or can be obtained from natural sources.

For example, compounds IV.a and IV.b, where Y is hydroxyl, are readily available commercially or can be obtained from natural sources.

Compounds IV.a and IV.b wherein Y is a leaving group other than hydroxyl as defined above can be prepared from the corresponding alcohol precursors by conventional nucleophilic substitution reactions. These nucleophilic reactions can be carried out under conventional reaction conditions which are well known to those skilled in the art.

Typically, the reaction in step c) according to the present invention first proceeds to form a Friedel-Crafts alkylation product. In the event that the hydroxyl groups adjacent to the alkylation position are not protected, the Friedel-Crafts alkylation reaction is usually followed by a subsequent ring closing reaction (double bond intramolecular hydroxyalkylation) to form a fused six-membered ring containing an oxygen atom. If desired, the Friedel-Crafts alkylation intermediate can also be isolated and the ring closing reaction can be carried out in a separate step. However, it is preferred that the Friedel-Crafts alkylation and the ring-closure reaction be carried out in one step.

According to a preferred embodiment of the present invention, the reaction in step c) is carried out with removal by distillation of at least one part of the water formed during the reaction. As mentioned above, the distillative removal of the water formed during the reaction can be facilitated by using an apolar hydrocarbon solvent (HS) such as cyclohexane, heptane, octane or toluene in addition to the polar aprotic solvent (PS) in step c) because apolar hydrocarbon solvents (HS) often form azeotropic mixtures with water. To do this, steam is removed from the reaction system and condensed. If the vapor consists of an azeotropic mixture of water with the organic solvent used in step c) and/or another component of the reaction mixture of step c), or if the water contains significant amounts of product or starting material, the resulting condensate is usually subjected to phase separation to obtain an aqueous phase and an organic phase. To do this, the condensate is usually fed into a phase separator (decanter), where mechanical separation leads to its decomposition into two phases, which can be extracted separately. If necessary, a water-immiscible organic solvent, preferably the organic solvent used in step c), is added to the condensate before passing the condensate to the phase separator. The aqueous phase is removed and discarded, and the organic phase, at least to some extent, is returned to the reaction system. "Return to the reaction system" means that the organic phase passes into any desired at least one reactor of the reaction system.

Any of the suitable condensers may be used to condense or partially condense steam. They can be cooled with any coolant. Preference is given to air-cooled and/or water-cooled condensers, with particular preference given to air-cooled condensers.

The reaction in step c) can be carried out either in batch mode (intermittent mode), as described above, or in continuous mode. Preference is given to carrying out the reaction in step c) continuously.

If the reaction in step c) is carried out in a batch (discontinuous) mode, the reactants and catalyst are usually placed in a suitable reaction vessel, for example, a stirred vessel or a loop reactor at the temperatures indicated above, until the desired conversion is achieved. The reaction time may be from 0.5 to 30 hours, preferably from 1 to 20 hours, depending on the amount of added catalyst.

Preferably, the reaction in step c) is carried out in such a way that first the organic solvent and the condensation catalyst, preferably an acidic heterogeneous catalyst, in particular a treated bentonite catalyst, are placed in a suitable reaction vessel, for example a stirred vessel or a loop reactor, and heated to a temperature reactions. If necessary, the resulting suspension is stored at the reaction temperature for several minutes, for example, for 1, 2, 5, 10, 15 or 20 minutes until the suspension is cooled to below 80°C. During these pretreatment steps, an inert gas, preferably argon or nitrogen, is introduced into the device to ensure that the device is free of oxygen. Thereafter, compound (III) was added in one portion to the preheated solvent/catalyst slurry, and the resulting mixture was heated to the reaction temperature. The compound IV.a or IV.b, optionally dissolved in an apolar hydrocarbon solvent (HS), is then added to the reaction mixture. Typically, compound IV.a or IV.b is added step by step to the reaction mixture containing organic solvent, condensation catalyst and compound (III), in several portions, for example, in the form of 2, 3, 4, 5, 10, 15 or 20 portions, or dosed continuously. Preferably, compound IV.a or IV.b is dosed continuously. The rate of addition of compounds IV.a or IV.b in the reaction mixture is usually in the range of 0.2 to 5% v/min, preferably in the range of 0.3 to 3% v/min, in particular in the range of 0.5 to 2 vol.%/min, based on the total volume of compounds IV.a or IV.b

Depending on whether only a polar aprotic solvent (PS) or a mixture consisting of a polar aprotic solvent (PS) and an apolar hydrocarbon solvent (HS) is used as the organic solvent in step c), the desired reaction product is separated from the resulting reaction mixture phase separation and/or extraction with apolar hydrocarbon solvent (HS). Thus, two phases are obtained, i.e. a PS phase containing mainly the condensation catalyst and ultimately unreacted compound (III), and an HS phase containing mainly the desired reaction product and ultimately unreacted compound IV.a or IV .b. After phase separation and/or extraction, the reaction product can be purified by chromatographic methods, distillation and/or crystallization, preferably distillation, or the reaction product can be directly subjected to the next reaction step d).

In the case of using a homogeneous condensation catalyst in step c) of the method according to the present invention, the reaction mixture can also be neutralized with an aqueous alkaline solution and/or water in order to remove the homogeneous condensation catalyst from the reaction mixture by extraction.

In the case that an acidic heterogeneous catalyst, in particular a treated bentonite catalyst, is used in step c) of the process according to the present invention, the acidic heterogeneous catalyst, in particular a treated bentonite catalyst, is preferably separated from the reaction mixture or the PS phase after completion of the reaction. and reused in the next reaction in step c).

To separate the acidic heterogeneous catalyst, in particular the treated bentonite catalyst, from the reaction mixture or the PS phase, in particular, all methods known to the person skilled in the art that are suitable for separating solids from liquid mixtures can be used. Preferably, the catalyst is removed from the resulting reaction mixture by filtration. After separation, the acidic heterogeneous catalyst, in particular the treated bentonite catalyst, is dried under an inert gas stream, preferably under a nitrogen stream. The drying time of an acidic heterogeneous catalyst, in particular a treated bentonite catalyst, in an inert gas stream can vary over a wide range, depending on the nature of the solvent used in the reaction of step c). The drying time of the acidic heterogeneous catalyst in an inert gas stream is typically in the range of several minutes to several days, ie 5 minutes to 5 days. The drying time of the acidic heterogeneous catalyst in an inert gas stream may be, for example, 10 minutes, 30 minutes, 1 hour, 5 hours, 12 hours, 1 day, 3 days or 5 days.

According to another preferred embodiment of the present invention, the PS phase containing mainly the condensation catalyst and ultimately the unreacted compound (III), which is obtained after separation and/or extraction of the reaction mixture obtained in step c), with the apolar hydrocarbon solvent HS), directly reused in the further reaction in step c).

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 containing the treated bentonite catalyst in the form of a fixed bed or a moving bed, preferably in the form of a fixed bed, in which, for example, serves a mixture of organic solvent with compound III and compound IV.a or IV.b. In the preferred fixed bed mode of operation, the reactor may be operated in settling mode, i.e. the reaction mixture is directed from bottom to top, or in jet flow mode, i.e. the reaction mixture will flow through the reactor from top to bottom. The water formed during the reaction is removed by removing steam from the top of the reactor, which is condensed and separated into an organic phase, ultimately containing an apolar hydrocarbon solvent (HS) and minor amounts of unreacted compound III and/or reaction product, and an aqueous phase, as described above. The organic phase is optionally returned to at least one reactor. A reaction mixture stream containing polar aprotic solvent (PS), apolar hydrocarbon solvent (HS) if present, reaction product and ultimately unreacted compound III is withdrawn from the bottom of the reactor. Depending on whether only a polar aprotic solvent (PS) or a mixture consisting of a polar aprotic solvent (PS) and an apolar hydrocarbon solvent (HS) is used as the organic solvent in step c), the desired reaction product is separated from the resulting reaction mixture by separation phases and/or extraction with an apolar hydrocarbon solvent (HS). The reaction product may be purified or the reaction product may be directly subjected to the next reaction step.

The hourly space velocity of the catalyst in the reaction of step c) is in the range of 0.1 to 50 kg of compound IV.a or IV.b per kg of catalyst per hour, in particular in the range of 0.2 to 30 kg of compound IV.a or IV.b per kg of catalyst per hour.

The at least one reactor may be selected from any desired reactors that are suitable for carrying out heterogeneously catalyzed liquid phase chemical reactions.

Suitable reactors are non-back-mixed reactors such as tubular reactors or shut-down time containers provided with internals, but preferably back-mixed reactors such as stirred or loop reactors. However, it is also possible to use combinations of consecutive back-mixed and non-back-mixed reactors.

If necessary, several reactors can also be combined into a multi-stage device. Such reactors are, for example, loop reactors with built-in sieve trays, cascade containers, tubular reactors with an intermediate feed point or columns with a stirrer.

Stage d):

If R ⁴ in compound I is selected from C ₁ -C ₆ alkanoyl, the condensation product obtained in step c) is reacted with a C ₂ -C ₇ carboxylic acid or C ₂ -C ₇ carboxylic acid anhydride in the presence of an esterification catalyst .

Suitable esterification catalysts that can be used in step d) of the process of the present invention are well known to those skilled in the art. Suitable esterification catalysts are, for example, metal based catalysts, eg iron, cadmium, cobalt, lead, zinc, antimony, magnesium, titanium and tin based catalysts in the form of metals, metal oxides or metal salts such as metal alkoxylates; mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid; or organic sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.

Alternatively, the condensation product obtained in step d) is reacted with an activated C ₂ -C ₇ carboxylic acid in the presence of a base.

Suitable activated C ₂ -C ₇ -carboxylic acids which can be used in step d) of the process according to the present invention are, for example, C ₂ -C ₇ -carboxylic acid halides such as C ₂ -C ₇ - chlorides, bromides or iodides. carboxylic acid.

Suitable bases which can be used in step ii) are, for example, organic bases such as, for example, tertiary amines, eg trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine and the like. or basic N-heterocycles such as morpholine, pyridine, lutidine, DMAP, DABCO, DBU or DBN.

The individual reaction conditions for these esterification reactions are well known to those skilled in the art.

Preferably, in step d) of the process according to the invention, the condensation product obtained in step b) is reacted with a C ₂ -C ₇ -carboxylic acid or with a C ₂ -C ₇ -carboxylic acid anhydride in the presence of an esterification catalyst.

According to a preferred embodiment of the present invention, the esterification catalyst used in step d) is selected from acidic heterogeneous catalysts as defined above.

According to a more preferred embodiment of the present invention, step d) is carried out in the presence of the same acidic heterogeneous catalyst as used in step c).

Preferably, according to this more preferred embodiment, the acidic heterogeneous catalyst used in steps c) and d) is separated from the reaction mixture after completion of the reaction in step d) and reused in the further reaction in step c). The recycling of heterogeneous condensation catalysts is carried out as described above in step c) for the treated bentonite catalyst.

According to an even more preferred embodiment of the present invention, the esterification reaction in step d) is carried out in the presence of a treated bentonite catalyst as defined above, in particular in the presence of a treated bentonite acid catalyst.

According to a specific embodiment of the present invention, the reaction in step c) and the esterification reaction in step d) are carried out in the presence of the same treated bentonite catalyst, in particular in the presence of a treated bentonite acid catalyst.

Preferably, also according to this particular embodiment, the treated bentonite catalyst used in steps c) and d) is separated from the reaction mixture after completion of the reaction in step d) and reused in the further reaction in step c) as described above for step c).

According to a specific embodiment of the present invention, the reactions in steps c) and d) are carried out in the presence of at least one polar aprotic solvent (PS) as defined above, or in a solvent mixture consisting of at least one polar aprotic solvent (PS), as defined above, and at least one apolar hydrocarbon solvent (HS) as defined above.

According to a more specific embodiment of the present invention, steps c) and d) are carried out in the presence of a carbonate solvent.

According to another specific embodiment of the present invention, the reaction of steps c) and d) is carried out in a carbonate solvent/apolar hydrocarbon solvent mixture as described above.

Suitable and preferred carbonate solvents, as well as suitable and preferred apolar hydrocarbon solvents (HS), if present, are as defined above.

Even more preferably, in this particular embodiment, step d) is carried out in the same carbonate solvent and, if present, the same apolar hydrocarbon solvent (HS) as used in step c). In particular, the reaction mixture obtained in step c) is used directly in the reaction of step d), that is, step c) and step d) are carried out as a reaction in one reactor.

The reaction product, i.e. the compound of formula (I) obtained in step d), can be worked up in the usual manner, for example by filtering off any solid catalyst, if present, adding an apolar hydrocarbon solvent (HS) if necessary, separating the phases and, if necessary, , purification of crude products by chromatographic methods, distillation or recrystallization.

According to a particular embodiment of the present invention, steps b), c) and d) are carried out in the same carbonate solvent and, if present, in the same apolar hydrocarbon solvent (HS). Preferably, according to this particular embodiment, the reaction mixture obtained in step b) is directly used in the reaction in step c) after removal of the hydrogenation catalyst, and the reaction mixture obtained in the next step c) is directly used in the reaction in step d).

The method according to the present invention provides compounds (I) with high yields and selectivity. Typically, compounds (I) are further purified by recrystallization, distillation, if applicable, or by chromatographic methods.

In general, only minor amounts of by-products are obtained.

Common by-products that are obtained using the methods described in the prior art for the preparation of compounds of general formula (I) are, for example, diene compounds of general formula X.1 to X.3, which are formed from compounds IV. a or IV.b as a result of unwanted elimination reactions, as shown in Scheme 4.

гдеScheme 4:

Where

X has a value as defined above, and

X-2 is preferably selected from fragments of formulas X-2.a and X-2.b

Where

n is an integer from 0 to 2 and

* indicates the point of attachment to the rest of the molecule.

The formation of these dienes is generally increased when carboxylic acids such as oxalic acid, tartaric acid or citric acid are used as the condensation catalyst. These acids are capable of forming ester intermediates with compounds IV.a or IV.b., which can be easily eliminated to compounds of general formula X. 1 to X.3.

Diene compounds of general formula X. 1 - X. 3 can also be reacted with compounds (III) in step c). However, the reaction proceeds very slowly compared to the reaction with compounds IV.a or IV.b. Thus, the formation of diene compounds X. 1 - X.3 should be avoided.

In addition, benzofuran isomers of formula XI-1 can be formed by reacting hydroquinone compounds (III) with compounds IV.a, as shown in Scheme 5, which are difficult to separate from the desired compounds (I).

Scheme 5:

Using the method of the present invention, the formation of these common by-products can be successfully suppressed.

The following examples provide further explanation of the present invention. These examples are not to be understood as limiting the present invention.

Examples

Abbreviations:

GC means gas chromatography,

HPLC high performance liquid chromatography,

TMH means trimethylhydroquinone (2,3,5-trimethylhydroquinone),

TMQ means trimethylquinone (2,3,5-trimethylquinone),

PC propylene carbonate

EC ethylene carbonate

1. Analytical research:

1.1 Determination of product purity:

The purity of the products was determined by determining the area % by gas chromatography. The yield of compounds I and II was determined by determining the % mass by GC method, using docosan as an internal standard and n-heptane as a solvent.

GC system: Agilent 6980N;

GC column: Agilent DB-1: 30 m (length), 0.25 mm (inside diameter), 0.25 micrometer (film thickness);

Temperature program: 80°C - 350°C at 10°/min, 350°C for 10 minutes, total cycle time: 37 minutes.

The amount of compounds (III) in the (final) reaction mixture was determined by determining the % mass by HPLC:

HPLC system: Agilent Series 1200

HPLC column: Zorbax Eclipse RAS, 1.8 µm, 50*4.6 mm from AgilentÒ

Eluent:

A: water with 0.1 vol.% H ₃ PO ₄ ;

B: acetonitrile

Detector: UV detector λ=210 nm, BW=5 nm, flow rate: 1.2 ml/min, injection: 2 µl, temperature: 60°C, operating time: 20 min, pressure: approx. 130 bar.

1.2 Determination of surface area by BET:

System: Quantachrome Autosorb Automated Gas Sorption System 6B, serial-#: 10896010901;

Software: Autosorb for Windows® for AS-3 and AS-6 version 1.22;

Sample weight: 0.28-0.43 g of solid catalyst (eg treated bentonite catalyst);

Bath temperature: 77.4 K;

Duration: 64 - 106.7 minutes;

Measurement gas: nitrogen; gas purity: nitrogen 5.0;

Drying before measurement: centrifugal vane pump and finally turbomolecular pump for 16 hours at 120°C, <1 mbar;

System parameters: cross-sectional area 16.2 Å/molec;

Multipoint BET: 5 points r/r ₀ ; 0.05≤r/r ₀ ≤0.30.

1.3 Determination of the residual acidity of the solid catalyst (mg KOH/g solid catalyst):

The determination of the residual acidity of a solid catalyst (for example, a catalyst based on treated bentonite) was carried out in such a way that first an aqueous suspension was prepared with a certain amount of solid catalyst as follows: from 1.0 g to 1.5 g of solid catalyst was suspended in 50 ml of deionized water and stirred for 1 h. A pre-calibrated KC1-pH electrode was placed in this suspension. An aqueous solution of NaOH at a certain concentration of 0.1 mol/l was then titrated into this aqueous suspension until the pH of the solid catalyst suspension was in the alkaline range (inflection point), which is the end point of the titration. The volume VI in ml of NaOH solution used to reach the inflection point was recorded.

In addition, a blank determination was carried out in the same manner using 50 ml of deionized water. The volume of NaOH V2 solution used in ml was recorded.

The residual acidity of the solid catalyst sample (in mg KOH/g solid catalyst), which is then determined as the total acid number, is calculated using the following formula:

56.1 g/mol is a constant (molar mass of KOH in g/mol);

m1 is the mass in grams of the test sample, i.e. solid catalyst sample;

V1 is the volume in milliliters of NaOH solution used to neutralize the catalyst slurry (volume to inflection point);

V2 is the volume in milliliters of the NaOH solution used in the blank determination (volume to inflection point - typically not used/blank is typically zero);

C is the concentration of the NaOH solution in moles per litre;

t is the titer of the NaOH solution.

The determination of the residual acidity is repeated once and thus determined twice.

1.4 Determination of catalyst density:

Device: AccuPyc II 1340 Series Pycnometer

Brand: Micromeritics

Inert gas: helium

Sample weight: 2.1-4.8 g

Sample chamber: 10 ml

The program "Conditions of analysis" was used, which included 99 cycles and each cycle with 5 repetitions.

Before measurements, the samples were treated for 16 h at 120°C in a vacuum of <1 mbar.

Density [g/cm ³ ]=sample mass [g] / sample volume [cm ³ ]

1. Examples of receipt

Origin and specification of applied acid catalyst based on treated bentonite:

The acid treated bentonites used as catalysts in the following preparations are either acid treated bentonites from BASF SE which were developed in-house (BASF SE internal material) or acid treated bentonites available from Sigma Aldrich or from Clariant Product GmbH.

Bentonite-based catalysts with the following specifications were used:

*) determined by Karl-Fischer titration and/or by weight loss on drying (16 h at 120°C and pressure <1 mbar).

To prepare the acid-treated bentonite catalyst from BASF SE (Catalysts 1-5), Aberdeen clay, known for its high quality, was used as the starting natural bentonite. These bentonites are activated with sulfuric acid and then converted into the final granular mineral catalysts.

General reaction procedure and notes:

The progress of the reaction is followed by thin layer chromatography and GC.

Stage 1: Restore TMQ to TMN

Step 2: Friedel-Crafts Alkylation and Condensation

Unless otherwise noted, all reactions are carried out in a glass flask using a paddle and a Dean-Stark trap which

- if a mixture of HS and PS is used as a solvent, fill with the HS used,

- in the case of using PS as a solvent that does not form an azeotrope with water, it remains empty, and

- in the case of using a solvent that forms an azeotrope with water, it is filled with the solvent used (as opposed to water), which is azeotropically removed with water.

Stage 3: Esterification

2.1 Preparation of 2,3,5-trimethylhydroquinone (step 1)

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 on activated carbon (10%, 0.38 mmol, 0.01 eq.) was added and the resulting reaction mixture was hydrogenated for 23 hours at 8 bar hydrogen pressure and at 64°C. After a reaction time of 6 h the filtered reaction mixture is only a slightly yellowish solution, after a reaction time of 23 h

- colorless solution. As a result of the GC analysis, we received:

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

Obtaining 2,3,5-trimethylhydroquinone

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 on activated carbon (10%, 2.6 mmol, 0.03 eq.) was added and the resulting reaction mixture was hydrogenated for 23 hours at 8 bar hydrogen pressure and 88°C. Then, the reaction mixture was immediately filtered and 83.3 g of an almost colorless eluate (97.6 GC-area-% TMH and 0.05 GC-area-% TMQ) was obtained.

Preparation of fully racemic alpha-tocopherol (catalyst 2):

To crude TMP in propylene carbonate (81.4 g after analytical analysis, take: 100% yield: 92.85 mmol, 1.7 eq.) 0.19 g of catalyst 2 (dried overnight at 120°C / 50 mbar in vacuum drying oven) / g TMP (2.7 g of catalyst 2) was added. The reaction mixture was brought to 120-125°C and stirred for 15 min. Then, 16.45 g of isophytol (97.4%, 54 mmol) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125°C) while removing the water generated during the reaction by distillation. After a subsequent reaction time of 4 h at 125°C, at room temperature overnight, and another 4 h at 125°C, the reaction mixture was brought to room temperature, 20 ml of heptane was added, further stirred for 15 min 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, the propylene carbonate phase was extracted with 4×25 ml of heptane. The combined heptane phases were dried over sodium sulfate. The solvent was removed under reduced pressure 50° C./5 mbar plus 15 min oil vacuum pump. 24.09 g of crude alpha-tocopherol (91.6% area GC and 85.66% wt GC) was obtained as a dark red clear viscous residue in 89% yield (based on % wt GC over two steps) . Each stage had an average yield of 94.5%.

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

233.57 g (193.99 ml) of propylene carbonate and 0.22 g of catalyst 1 (dried at 120° C. overnight, 50 mbar)/g of TMP (21.75 g of catalyst 1) were heated under a stream of nitrogen gas to 120-125° C and stirred for 15 min. The suspension was then cooled to <90° C. and 100.11 g (652.5 mmol) trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 136.35 g (162.13 ml) of isophytol (447.9 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125 °C) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 120-125° C., the reaction mixture was cooled to room temperature. The mixture was filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 1. The filter cake was washed with 6 x 130 ml heptane and 3 x 130 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×190 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50-55°C/5 mbar plus 15 min. % mass according to GC) was obtained as a transparent viscous dark red residue. This corresponds to a yield of 98%.

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

138.08 g (141.91 ml) of diethyl carbonate and 0.22 g of catalyst 1 (dried at 120° C. overnight, 50 mbar)/g TMH (7.5 g of catalyst 1) were heated under a stream of nitrogen gas to 120-123 °C and stirred for 15 min. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.76 g (54.41 ml) of isophytol (150 mmol, 97.2% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 124-119°C ) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 120-125° C., the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter loaded with zeolite to remove Catalyst 1. The filter cake was washed with 6×45 ml of heptane. All mother liquors and washing solutions were collected and combined. The eluate from which precipitation was observed was further filtered and the solvent was removed under reduced pressure at 50-55°C / 5 mbar plus 15 min oil vacuum pump: 68.84 g of crude alpha-tocopherol (84.8 area% according to GC and 78.79% by weight according to GC) was obtained as a reddish brown viscous cloudy residue. This corresponds to a yield of 84%.

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

80.55 g (71.92 ml) of gamma-butyrolactone and 0.22 g of catalyst 1 (dried at 120° C. overnight, 50 mbar)/g TMH (7.5 g of catalyst 1) were heated under a stream of nitrogen gas to 120 -125°C and stirred for 15 minutes. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.76 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125°C ) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 120-125° C., the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. Then, the mixture was filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 1. The filter cake was washed with 6×45 ml of heptane and 3×45 ml of gamma-butyrolactone. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The gamma-butyrolactone phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles removed under reduced pressure at 50-55°C/5 mbar plus 15 min oil vacuum pump: 68.71 g crude alpha-tocopherol (89.7 area % according to GC and 38% by weight according to GC) was obtained as a dark red clear viscous residue. This corresponds to a yield of 83%.

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

This reaction was carried out without removal of water and thus without a Dean-Stark trap. The apparatus used consists of a flask, a paddle stirrer and a reflux condenser.

80.55 g (66.9 ml) of propylene carbonate and 0.22 g of catalyst 1 (dried at 120° C. overnight, 50 mbar)/g TMH (7.5 g of catalyst 1) were heated under a stream of nitrogen gas to 120-125 °C and stirred for 15 min. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.86 g (54.5 ml) of isophytol (150 mmol, 97% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125°C). After a subsequent reaction time of 4 hours at 123-124°C, at room temperature overnight, and another 2 hours at 124°C, the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter loaded with zeolite to remove Catalyst 1. The filter cake was washed with 6×45 ml heptane and 3×45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50-55°C/5 mbar plus 15 min oil vacuum pump: 66.04 g crude alpha-tocopherol (92.7 area % according to GC and .55 wt % according to GC) was obtained as a clear dark red viscous residue. This corresponds to a yield of 86%.

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

103.14 g (78.08 ml) of ethylene carbonate, 47.73 g (67.9 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 2 (all dried at 120°C) overnight, 50 mbar)/g TMN (22.5 g Catalyst 2) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction mixture temperature: 120-125° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 123-126°C, the reaction mixture was cooled to <60°C and 50 g of propylene carbonate was added. Then, the reaction mixture was further cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2. The filter cake was washed with 3×45 ml of octane and 3×45 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The ethylene/propylene carbonate phase was extracted with 4×65 ml of octane. The combined octane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50-55°C/5 mbar plus 15 min oil vacuum pump: 63.66 g crude alpha-tocopherol (95.5 area % according to GC and 91 44 wt % according to GC) was obtained as a dark red clear viscous residue. This corresponds to a yield of 90%.

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

232.63 g (193.21 ml) of propylene carbonate, 118.06 g (167.9 ml) of n-octane (plus 60 ml of octane in a Dean-Stark trap) and 0.22 g of catalyst 2 (all dried at 120°C) overnight, 50 mbar)/g TMN (21.75 g Catalyst 2) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction mixture temperature: 120-125° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 99.7 g (625.5 mmol) trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 123°C. Then, 137.22 g (163.17 ml) of isophytol (435 mmol, 94% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 125-123°C) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 123-125°C, at room temperature overnight, and another 2 hours at 125°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2 The filter cake was washed with 3 x 130 ml heptane and 3 x 130 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×190 ml of heptane. The combined heptane/n-octane phases were dried over sodium sulfate and the volatiles removed under reduced pressure at 50-55°C/5 mbar plus 15 min oil vacuum pump: 199.16 g crude alpha-tocopherol (92.6% area according to GC and 87.57% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 93%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.22 g of catalyst 2 (dried at 120° C. overnight, 50 mbar) / g of TMN (7.5 g of catalyst 2) were heated to 50 - 90° C. and 34 .52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated to 150° C. and 45.67 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours. reaction 6 h the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2. The filter cake was washed with 6×45 ml heptane and 3×45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum: 65.61 g crude alpha-tocopherol (92.5 area% according to GC and 84.73 % mass according to GC) was obtained as a transparent viscous dark red residue. This corresponds to a yield of 86%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.33 g of catalyst 2 (dried at 120° C. overnight, 50 mbar)/g TMP (11.25 g of catalyst 2) were heated under a stream of nitrogen gas to 120-125 °C and stirred for 15 min. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) trimethylhydroquinone (3 eq.) was added. The mixture was then heated again to 120-125°C. Then, 22.88 g (27.21 ml) of isophytol (75 mmol, 97.2% pure, 1 eq.) was continuously added to the reaction mixture over a period of 1 hour (reaction mixture temperature: 121-125°C ). After a subsequent reaction time of 6 hours at 120-125° C., the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2. The filter cake was washed with 6×45 ml heptane and 3×45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 33.99 g crude alpha-tocopherol (95.2 area% according to GC and 88.45% wt according to GC) was obtained as a clear dark red viscous residue. This corresponds to a yield of 93%.

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

80.55 g (66.9 ml) of propylene carbonate, 39.79 g (58.18 ml) of n-heptane (plus 60 ml of heptane in a Dean-Stark trap) and 0.22 g of catalyst 2 (all dried at 120°C) overnight, 50 mbar)/g TMN (7.5 g Catalyst 2) was heated under a stream of nitrogen gas to slightly reflux n-heptane (reaction temperature: 100° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.52 g (225 mmol) trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 100°C. Then, 45.86 g (54.52 ml) of isophytol (150 mmol, 97% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 100-102° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 103-104°C, at room temperature overnight, and another 2 hours at 102°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2 The filter cake was washed with 3 x 45 ml heptane and 3 x 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane/n-octane phases were dried over sodium sulfate and the volatiles removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 63.99 g crude alpha-tocopherol (88.9 area % according to GC and 85.26% by weight according to GC) was obtained as a dark red clear viscous residue. This corresponds to a yield of 84%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.22 g of catalyst 3 (dried at 120° C. overnight, 50 mbar)/g TMP (7.5 g of catalyst 3) were heated under a stream of nitrogen gas to 120-125 °C and stirred for 15 min. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.86 g (54.52 ml) of isophytol (150 mmol, 97% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 122-125°C). After a subsequent reaction time of 4 hours at 120-125°C, at room temperature over the weekend, and another 2 hours at 120-125°C, the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. Then, the mixture was filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 3. The filter cake was washed with 6×45 ml of heptane and 3×45 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 65.43 g crude alpha-tocopherol (94.1 area% according to GC and 87.05% mass according to GC) was obtained in the form of a transparent viscous dark red residue. This corresponds to a yield of 88%.

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

80.22 g (66.63 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 4 (all dried at 120°C) overnight, 50 mbar)/g TMN (22.5 g Catalyst 4) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction mixture temperature: 120-122° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 118-120° C.) while removing water formed during the reaction, through distillation. After a subsequent reaction time of 6 hours at 121-124° C., the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite 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 washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 64.06 g crude alpha-tocopherol (90.5 area % according to GC and 86, 86% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 86%.

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

80.22 g (66.63 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 5 (all dried at 120°C) overnight, 50 mbar)/g TMN (22.5 g Catalyst 5) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction mixture temperature: 120-121° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 115-120° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 119-123°C, at room temperature over the weekend, and another 2 hours at 122°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove the 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 washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 65.08 g crude alpha-tocopherol (87.3% area according to GC and 85, 15% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 86%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.33 g of catalyst 6 (undryed)/g of TMN (11.25 g of catalyst 6) were heated under a stream of nitrogen gas to 120-125° C. and stirred for 15 minutes. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.67 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 1 hour (reaction mixture temperature: 122-125°C ). After a subsequent reaction time of 6 hours at 122-125° C., the reaction mixture was cooled to room temperature. 45 ml of heptane and celite were added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter to remove celite and catalyst 6. The filter cake was washed with 6 x 45 ml heptane and 3 x 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 64.75 g crude alpha-tocopherol (86.7 area% according to GC and 81.19% mass according to GC) was obtained in the form of a transparent viscous dark red residue. This corresponds to a yield of 81%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.33 g of Catalyst 7 (undryed)/g of TMN (11.25 g of Catalyst 7) were heated under a stream of nitrogen gas to 120-122° C. and stirred for 15 min. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.67 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 1 hour (reaction mixture temperature: 120-124°C ). After a subsequent reaction time of 6 hours at 120-125° C., the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. Then, the mixture was filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 7. The filter cake was washed with 6×45 ml of heptane and 3×45 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 64.76 g of crude alpha-tocopherol (91.8 area% according to GC and 86.01% mass according to GC) was obtained in the form of a transparent viscous dark red residue. This corresponds to a yield of 86%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.44 g of catalyst 8 (undryed)/g of TMN (15 g of catalyst 8) were heated under a stream of nitrogen gas to 120° C. and stirred for 15 minutes. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.67 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 121-125°C ). After a subsequent reaction time of 4 hours at 121-125°C, at room temperature overnight, and another 2 hours at 120-125°C, the reaction mixture was cooled to room temperature. 45 ml of heptane was added to the reaction mixture, which was stirred for 15 min at room temperature. The mixture was then filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 8. The filter cake was washed with 6 x 45 ml heptane and 4 x 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 64.27 g crude alpha-tocopherol (75.8 area% according to GC and 87.13% mass according to GC) was obtained in the form of a transparent viscous dark red residue. This corresponds to a yield of 87%.

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

80.55 g (66.9 ml) of propylene carbonate and 0.33 g of catalyst 9 (undryed)/g of TMN (11.25 g of catalyst 9) were heated under a stream of nitrogen gas to 120° C. and stirred for 15 minutes. The suspension was then cooled to <90° C. and 34.52 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 120-125°C. Then, 45.67 g (54.3 ml) of isophytol (150 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 1 hour (reaction mixture temperature: 123-125°C ). After a subsequent reaction time of 6 hours at 125° C., the reaction mixture was analyzed: 30 area % according to GC THM, 5 area % according to GC phytadienones, 19 area % according to GC wick-TMN, no alpha-tocopherol. The reaction mixture was removed.

2.19 Continuous preparation of 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (fully racemic alpha-tocopherol) (Step 2; catalyst 9)

Used catalyst:

Montmorillonite K10 (pH 3-4, surface area) "diluted" with Celite in a 1:1 weight ratio from Thales Nano, packaged in a cartridge (so-called CatCart). The CatCart cartridge used was 70×4 mm and had a fill weight of 459 mg.

Continuous receipt procedure:

8 wt. % solution of TMN in bis(2-methoxyethyl) ether (=diglyme) and 10.4 wt. % solution of isophytol in bis(2-methoxyethyl)prosom ether (=diglyme) was pumped with a volume flow rate of 5 ml/h. onto the CatCart described above filled with K10 and Celite and heated to 200°C. The CatCart catalyst is in a vertical position.

Reaction progress was followed by GC: 61.3% area according to GC 2,5,7,8-tetramethyl-2-[4,8,12-trimethyltridecyl]-3,4-dihydro-2H-chromen-6-ol (fully racemic alpha-tocopherol) yielded 19.4 area % according to the GC of TMH and 13.5 area % according to the GC of phytadienes.

2.20 Preparation of fully racemic alpha-tocopherol acetate (Steps 1, 2 and 3):

Obtaining 2,3,5-trimethylhydroquinone

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 on activated carbon (10%, 2.63 mmol, 0.03 eq.) was added and the resulting reaction mixture was hydrogenated for 22.5 h at 8 bar hydrogen pressure and at 87-93°C. The reaction mixture was filtered at temperature and under nitrogen using a warm D4 glass vacuum filter with filter paper to give 84.31 g of eluate (95.3 GC area% of trimethylhydroquinone and 0.28 GC area% of trimethylquinone).

Preparation of fully racemic alpha-tocopherol (Catalyst 2)

To the crude trimethylhydroquinone in propylene carbonate from the first step (82.83 g, 1.73 eq., take 100% yield, 92.85 mmol) 0.19 g Catalyst 2 (dried at 120° C. overnight, 50 mbar )/g TMN (2.69 g Catalyst 2) was added and heated to 120°C and stirred for 15 min at 120-124°C. Then, 16.38 g (19.47 ml) of isophytol (53.8 mmol, 97.4% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 124-125 °C) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 5 hours at 125° C., the reaction mixture was stirred overnight at room temperature.

Preparation of fully racemic alpha-tocopherol acetate (Catalyst 2)

The brown suspension obtained in the second step was heated to 50° C. and 22.19 g (20.55 ml) of acetic anhydride (220 mmol, 4 eq.) was continuously added over a period of 15 minutes. Then, the reaction mixture was heated to 100° C. and stirred for 4 hours. After cooling to room temperature, 20 ml of heptane was added to the reaction mixture, which was stirred for 15 minutes. Then, the reaction mixture was filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2. The filter cake was washed with 6×20 ml of heptane and 3×20 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×25 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 25.71 g of crude fully racemic alpha-tocopherol acetate (89.28 area % according to GC) was obtained as a clear brown viscous residue. This corresponds to a yield of 90% (based on area % according to GC over 3 steps).

2.21 Preparation of fully racemic alpha-tocopherol acetate (Steps 2 and 3):

Preparation of fully racemic alpha-tocopherol (Catalyst 2)

100.29 g (83.3 ml) of propylene carbonate and 35.15 g of catalyst 2 were added and heated to 120-125° C. and stirred for 15 minutes. The suspension was then cooled to <90° C. and 22.92 g (150 mmol) trimethylhydroquinone (1.0 eq.) was added. The mixture was then heated again to 120°C. Then, 46.75 g (55.59 ml) of isophytol (154.5 mmol, 98% pure, 1.03 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-123 °C) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 123-124°C, the reaction mixture was stirred over the weekend at room temperature.

Preparation of fully racemic alpha-tocopherol acetate (Catalyst 2)

To the brown suspension obtained in the preceding step, 30.94 g (28.64 ml) of acetic anhydride (300 mmol, 2 eq.) was added continuously over a period of 10 minutes. Then, the reaction mixture was subjected to reactive distillation 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 brought to room temperature and 45 ml of heptane was added and the reaction mixture was stirred for 15 minutes. Then, filtered through a D4 glass vacuum filter to remove catalyst 2. The filter cake was washed with 3×45 ml of heptane and 3×45 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 71.79 g crude fully racemic alpha-tocopherol acetate (88.08 area % according to GC) was obtained as a brown transparent viscous residue containing 0.18 area% according to GC alpha-tocopherol. This corresponds to a yield of 89% (based on GC area % over 2 steps).

2.22 Influence of the drying temperature of the bentonite-based catalyst:

The effect of drying the bentonite-based catalyst prior to its use in the condensation reaction of TMP with IP was evaluated. Two reactions were carried out in analogy to example 2.8, except that here 225 mmol TMN was used instead of 625.5 mmol TMN (the amount of other reagents was adapted accordingly). The results are presented in table 1.

In the reaction of TMP with IP catalyzed by bentonite, drying the bentonite-based catalyst before use can improve catalyst turnover under the reaction conditions used in this case (for example, the PC/octane solvent mixture used).

The yield of alpha-tocopherol increases with increasing drying temperature of bentonite-based catalyst 2 from 79% (undried catalyst 2) to 93% (catalyst 2 dried at 120° C., 50 mbar, vacuum drying oven, overnight).

Example 2.22.1:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.6 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of octane in a Dean-Stark trap) and 0.74 g of catalyst 2 (undryed as is) / g TMN (25.43 g Catalyst 2) was heated under a stream of nitrogen gas to slight reflux (reaction temperature: 109° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to a slight return of reflux at 113°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 113-112° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 118-123° C., the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite 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 washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 59.31 g crude alpha-tocopherol (89.7 area% according to GC and 85, 47% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 79%.

Example 2.22.2:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.6 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 2 (dried at 60°C, overnight, 50 mbar)/g TMN (22.5 g Catalyst 2) was heated under a stream of nitrogen gas with slight reflux (reaction temperature: 115-117° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to a slight return of reflux at 118°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 119-117° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 120-124°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2. The filter cake was washed with 3×45 ml n-octane and 3× 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 61.10 g crude alpha-tocopherol (91.1% area according to GC and 86, 31% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 82%.

Example 2.22.3:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.6 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 2 (dried at 100°C, overnight, 50 mbar)/g TMN (22.5 g Catalyst 2) was heated under a stream of nitrogen gas to slight reflux (reaction temperature: 120-121° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to a slight return of reflux at 122°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 122-121° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 123-125° C., the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite 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 washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 65.91 g crude alpha-tocopherol (92.1 area % according to GC and 86, 47% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 88%.

Example 2.22.4:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.6 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 2 (dried at 120°C, overnight, 50 mbar)/g TMN (22.5 g Catalyst 2) was heated under a stream of nitrogen gas to slight reflux (reaction temperature: 120-121° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to a slight return of reflux at 121°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 115-121° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 6 hours at 118-123° C., the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite 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 washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 68.47 g crude alpha-tocopherol (91.2 area % according to GC and 87, 93% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 93%.

2.23 Bentonite Catalyst Recycling in Stage 2:

The possibility of recycling the bentonite-based catalyst used in the Friedel-Crafts alkylation and condensation reaction was evaluated. Several reactions were carried out as described below (example 2.23.1), in which the bentonite-based catalyst 2 was recovered in each reaction and reused in the next identical reaction.

The recycle of the bentonite-based catalyst 2 was five times for the Friedel-Crafts alkylation and condensation reaction under identical conditions (see Examples 2.23.1 - 2.23.6 in Table 2). The output can be reproduced within the error.

Example 2.23.1:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.63 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.65 g of catalyst 2 (dried at 120°C, overnight, 50 mbar)/g TMN (22.5 g Catalyst 2) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction mixture temperature: 120-121° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 121°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 116-121° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 120-122°C, at room temperature overnight, and another 2 hours at 122°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter to remove catalyst 2. The filter cake was washed with 3×45 ml of n-octane and 3×45 ml of propylene carbonate. The residue was aspirated to dryness and then dried under a stream of nitrogen overnight (wet weight: 40.20 g, dry weight: 38.11 g). The bentonite-based catalyst 2 thus recycled was used again in Example 2.23.2.

All mother liquors and washing solutions were collected and combined. The eluate phases 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 the volatiles removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 64.90 g crude alpha-tocopherol (92.0 area % according to GC and 86, 02% by weight according to GC) was obtained as a red transparent viscous residue. This corresponds to a yield of 86%.

Example 2.23.2:

Obtaining fully racemic alpha-tocopherol

80.22 g (66.63 ml) of propylene carbonate, 40.71 g (57.91 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 38.11 g of catalyst 2 from example 2.23.1. heated under a stream of nitrogen gas with slight reflux of n-octane (reaction mixture temperature: 120-124°C) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.38 g (225 mmol) of trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 122°C. Then, 45.39 g (53.97 ml) of isophytol (150 mmol, 98% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 119-122° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 2 hours at 122°C, at room temperature overnight, and another 4 hours at 123-124°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter to remove catalyst 2. The filter cake was washed with 3×45 ml of n-octane and 3×45 ml of propylene carbonate. The residue was sucked off to dryness and then dried under a stream of nitrogen over the weekend (dry weight: 33.33 g). The bentonite catalyst 2 thus recycled was used again in Example 2.23.3.

All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane/n-octane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 65.62 g crude alpha-tocopherol (92.6% area according to GC and 86.04 wt% according to GC) was obtained as a red, clear, viscous residue. This corresponds to a yield of 87%.

Examples 2.23.3 - 2.23.6 are carried out as described in Example 2.23.2.

2.24 Bentonite Catalyst Recycling in Steps 2 and 3:

Example 2.24.1:

Obtaining fully racemic alpha-tocopherol

100.29 g (83.3 ml) of propylene carbonate and 1.01 g of catalyst 2 (dried at 120° C., overnight, 50 mbar)/g TMN (23.17 g of catalyst 2) were added and heated to 123-124° C and stirred for 15 min. The suspension was then cooled to <90° C. and 22.92 g (150 mmol) trimethylhydroquinone (1.0 eq.) was added. The mixture was then heated again to 120°C. Then, 46.75 g (55.59 ml) of isophytol (154.5 mmol, 98% pure, 1.03 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-121 °C) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 120-125° C., the reaction mixture was stirred overnight at room temperature.

Preparation of fully racemic alpha-tocopherol acetate

To the brown suspension obtained in the preceding step, 30.94 g (28.64 ml) of acetic anhydride (300 mmol, 2 eq.) was added continuously over a period of 10 minutes. Then, the reaction mixture was subjected to reactive distillation for 1 h (310-335 mbar, internal temperature 74-88°C, transition temperature 28-45°C, oil bath temperature 100°C). The reaction mixture was stirred at room temperature at normal pressure over the weekend. Then, the reaction mixture was further subjected to reactive distillation for 1 h (310-335 mbar, internal temperature 64-67°C, transition temperature 32-34°C, oil bath temperature 75°C). Then, the reaction mixture was brought to room temperature and 45 ml of heptane was added and the reaction mixture was stirred for 15 minutes. Then, filtered through a D4 glass vacuum filter 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 off to dryness and then dried under a stream of nitrogen for 3 days (wet weight: 42.76 g, dry weight: 35.15 g). The bentonite-based catalyst 2 thus recycled was used again in Example 2.24.2.

All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 68.80 g crude fully racemic alpha-tocopherol acetate (79.90 area % according to GC) was obtained as an ochre-yellow transparent viscous residue containing 8.34% area according to GC alpha-tocopherol. This corresponds to a yield of 78% (based on GC area % over 2 steps).

Example 2.24.2:

Obtaining fully racemic alpha-tocopherol

100.29 g (83.3 ml) of propylene carbonate and 35.15 g of catalyst 2 from example 2.24.1 were added and heated to 120-125° C. and stirred for 15 minutes. The suspension was then cooled to <90° C. and 22.92 g (150 mmol) trimethylhydroquinone (1.0 eq.) was added. The mixture was then heated again to 120°C. Then, 46.75 g (55.59 ml) of isophytol (154.5 mmol, 98% pure, 1.03 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-123 °C) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 123-124°C, the reaction mixture was stirred over the weekend at room temperature.

Preparation of fully racemic alpha-tocopherol acetate

To the brown suspension obtained in the preceding step, 30.94 g (28.64 ml) of acetic anhydride (300 mmol, 2 eq.) was added continuously over a period of 10 minutes. Then, the reaction mixture was subjected to reactive distillation for 2 h (500 mbar, internal temperature 87-92°C, transition temperature 28-33°C, oil bath temperature 100°C). Then, the reaction mixture was brought to room temperature and 45 ml of heptane was added and the reaction mixture was stirred for 15 minutes. Then, filtered through a D4 glass vacuum filter to remove catalyst 2. The filter cake was washed with 3×45 ml of heptane and 3×45 ml of propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases were separated. The propylene carbonate phase was extracted with 4×65 ml of heptane. The combined heptane phases were dried over sodium sulfate and the volatiles were removed under reduced pressure at 50°C/5 mbar plus 15 min oil vacuum pump: 71.79 g crude fully racemic alpha-tocopherol acetate (88.08 area % according to GC) was obtained as a brown transparent viscous residue containing 0.18% area according to the GC of alpha-tocopherol. This corresponds to a yield of 89% (based on GC area % over 2 steps).

2.25 Recycling TMP used in excess in a carbonate solvent:

The possibility of recycling the unreacted excess of TMN along with the carbonate solvent used in the Friedel-Crafts alkylation and condensation reaction was evaluated. Two reactions were carried out in analogy to example 2.8, except that here 225 mmol TMN was used instead of 625.5 mmol TMN (amounts of other reagents were adapted accordingly) and that the unreacted excess of TMN was taken up in a carbonate solvent after completion of the reaction and repeated used in the next identical reaction. In both reactions the yields obtained were identical (examples 2.25.1 and 2.25.2 below, 87% yield in each case). Thus, the unreacted excess of TMP can be successfully recycled together with the carbonate solvent.

Example 2.25.1.

Obtaining fully racemic alpha-tocopherol

80.55 g (66.9 ml) of propylene carbonate, 40.9 g (58.18 ml) of n-octane (plus 60 ml of Dean-Stark octane) and 0.22 g of catalyst 2 (dried at 120°C, overnight, 50 mbar)/g TMN (7.5 g catalyst 2) was heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction temperature: 120-125° C.) and stirred for 15 min with reflux. The suspension was then cooled to <80° C. and 34.52 g (225 mmol) trimethylhydroquinone (1.5 eq.) was added. The mixture was then heated again to 121°C. Then, 45.86 g (54.52 ml) of isophytol (150 mmol, 97% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125° C.) at removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 124-125°C, at room temperature overnight, and another 2 hours at 125°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2 The filter cake was washed with 3 x 45 ml n-octane and 3 x 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases 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 the volatiles were removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 64.58 g crude alpha-tocopherol (93.1 area % according to GC and 87, 24% by weight according to GC) was obtained as a dark red transparent viscous residue. This corresponds to a yield of 87%. In addition, 172.31 g of a red transparent propylene carbonate phase containing 93.6 area % according to GC, 6.2% by weight according to HPLC of unreacted TMP was obtained. This corresponds to a recovery of 93% TMN (70 mmol out of 75 mmol applied TMN in excess). 85.87 g of this propylene carbonate phase was recycled to Example 2.25.2.

Example 2.25.2:

Obtaining fully racemic alpha-tocopherol

85.87 g of the propylene carbonate phase from example 2.25.1 (containing 5.32 g, 34.96 mmol, 0.23 eq. of TMS), 40.9 g (58.18 ml) of n-octane (plus 60 ml of octane in the trap Dean-Stark) and 0.22 g Catalyst 2 (dried at 120°C, overnight, 50 mbar)/g TMN (7.5 g Catalyst 2) were heated under a stream of nitrogen gas with a slight reflux of n-octane (reaction temperature mixture: 120-123°C) and stirred for 15 min with reflux. The suspension was then cooled to <80°C and 29.16 g (190.04 mmol) of trimethylhydroquinone (1.23 eq., in total: 1.46 eq.) was added. The mixture was then heated again to 120°C. Then, 47.2 g (56.12 ml) of isophytol (154.4 mmol, 97% pure, 1 eq.) was continuously added to the reaction mixture over a period of 2 hours (reaction mixture temperature: 120-125°C ) by removing the water formed during the reaction by distillation. After a subsequent reaction time of 4 hours at 124-125°C, at room temperature overnight, and another 2 hours at 125°C, the reaction mixture was cooled to room temperature and filtered through a D4 glass vacuum filter loaded with zeolite to remove catalyst 2 The filter cake was washed with 3 x 45 ml n-octane and 3 x 45 ml propylene carbonate. All mother liquors and washing solutions were collected and combined. The eluate phases 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 the volatiles removed under reduced pressure at 55°C/5 mbar plus 15 min oil vacuum pump: 65.70 g crude alpha-tocopherol (92.9 area % according to GC and 87 .71 wt % according to GC) was obtained as a clear dark red viscous residue. This corresponds to a yield of 87%. In addition, 196.85 g of a red transparent propylene carbonate phase containing 91.5 area % according to GC, 5.5% by weight according to HPLC of unreacted TMP was obtained. This corresponds to a recovery of >99% TMN (71 mmol out of 71 mols of TMN used in excess).

Claims (44)

1. Process for the preparation of a compound of general formula I

where R ¹ , R ² and R ³ are independently selected from hydrogen and methyl, R ⁴ is selected from hydrogen and C ₁ -C ₆ -alkanoyl and X is selected from C ₁ -C ₂₀ alkyl and C ₂ -C ₂₀ alkenyl, comprising the following steps: a) providing a quinone compound of general formula II

where R ¹ , R ² and R ³ have the meanings as defined above, b) catalytic hydrogenation of a quinone compound of formula II provided in step a), in the presence of hydrogen, a hydrogenation catalyst and in the presence of a carbonate solvent, to obtain a hydroquinone compound of general formula III

where R ¹ , R ² and R ³ have the meanings as defined above, c) reaction of the hydroquinone compound III provided in step b) with an unsaturated compound of general formula IV.a or IV.b

where X has the value as defined above, Y is selected from OH, halogen, -OR ¹¹ , -SR ¹² and -SO ₂ -R ¹² , R ¹¹ is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkanoyl and trifluoroacetyl and R ¹² is selected from C ₁ -C ₆ -alkyl, trifluoromethyl and phenyl, where phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 radicals selected from halogen and methyl, in the presence of a condensation catalyst, and d) if R ⁴ is selected from C ₁ -C ₆ -alkanoyl, the reaction of the condensation product obtained in stage c), with C ₂ -C ₇ carboxylic acid or with C ₂ -C ₇ -carboxylic acid anhydride in the presence of an esterification catalyst or the reaction the condensation product obtained in step c) with an activated C ₂ -C ₇ carboxylic acid in the presence of a base. 2. The method of claim 1 wherein the carbonate solvent is selected from at least one organic carbonate and from mixtures of at least one organic carbonate and at least one apolar hydrocarbon solvent. 3. The method according to claim 2, wherein the content of organic carbonate in mixtures consisting of at least one organic carbonate and at least one apolar hydrocarbon solvent is in the range from 50 to 99 wt.%, based on the total weight of the mixtures. 4. The method of claim 2 wherein the apolar hydrocarbon solvent is selected from the group consisting of linear and branched alkanes having 5 to 15 carbon atoms, cycloalkanes having 5 to 10 carbon atoms, and aromatic hydrocarbons having 6 to 12 carbon atoms. 5. Process according to claim 2, wherein the organic carbonate is selected from cyclic or linear carbonates of general formula V.a and V.b

where R ⁵ , R ⁶ and R ⁷ are independently selected from hydrogen, methyl and ethyl, R ⁸ is selected from hydrogen, phenyl and C ₁ -C ₁₅ -alkyl, where C ₁ -C ₁₅ -alkyl is unsubstituted or substituted with 1, 2 or 3 radicals selected from C ₁ -C ₃ -alkoxy, polyalkylene oxide, phenyl and phenoxy , And R ⁹ are independently selected from C ₁ -C ₄ alkyl. 6. The method according to any one of paragraphs. 2-5 wherein the organic carbonate is selected from ethylene carbonate, propylene carbonate, butylene carbonate, 2,3-propylene carbonate, isobutylene carbonate, dimethyl carbonate, diethyl carbonate and di-n-propyl carbonate. 7. The method according to p. 1, where in the compounds of general formulas I, II and III R ¹ , R ² and R ³ are methyl and R ⁴ , if present, is selected from hydrogen or ethanol. 8. The method according to p. 1, where X is methyl or has one of the following values X-1 - X-6

where * indicates the point of attachment to the chroman ring. 9. The method according to p. 1, where stage c) is carried out in a carbonate solvent. 10. The method of claim 1 wherein the same carbonate solvent is used in each of steps b) and c). 11. The method according to p. 1, where stage c) is carried out in a carbonate solvent used in stage b). 12. Process according to claim 1, wherein the reaction mixture obtained in step b) is used directly in the reaction in step c) after removal of the hydrogenation catalyst. 13. The method of claim 1, wherein the condensation catalyst used in step c) is selected from an acidic heterogeneous catalyst, and in particular from a treated bentonite catalyst. 14. The method according to any one of paragraphs. 1-13, where step d) is carried out in a carbonate solvent. 15. The method of claim 14 wherein steps b), c) and d) are carried out in the same carbonate solvent. 16. The process of claim 14 wherein the esterification catalyst used in step d) is selected from an acidic heterogeneous catalyst and in particular from a treated bentonite catalyst. 17. The process of claim 16 wherein steps c) and d) are carried out in the presence of the same treated bentonite catalyst. 18. The method of claim 17, wherein the reaction mixture obtained in step c) is used directly in the reaction of step d).