EP4077301A1 - Formation of alpha tocopherol from 2,3,6-trimethylphenol - Google Patents

Formation of alpha tocopherol from 2,3,6-trimethylphenol

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Publication number
EP4077301A1
EP4077301A1 EP20821237.3A EP20821237A EP4077301A1 EP 4077301 A1 EP4077301 A1 EP 4077301A1 EP 20821237 A EP20821237 A EP 20821237A EP 4077301 A1 EP4077301 A1 EP 4077301A1
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EP
European Patent Office
Prior art keywords
formula
solvent
process according
compound
carbon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20821237.3A
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German (de)
French (fr)
Inventor
Werner Bonrath
Thomas Netscher
Michael Schneider
Jonathan Alan Medlock
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DSM IP Assets BV
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DSM IP Assets BV
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Publication of EP4077301A1 publication Critical patent/EP4077301A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
    • C07D317/38—Ethylene carbonate

Definitions

  • the present invention relates to the field of the synthesis of a-tocopherol.
  • a-Tocopherol is an important substance and is part of vitamin E.
  • the major reaction pathway in its chemical synthesis uses a condensation of (iso)phytol with 2,3,5-trimethylhydroquinone (TMHQ) as disclosed for example in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, 7 th Edition, “Vitamins”, page 44 -46.
  • TMHQ 2,3,5-trimethylhydroquinone
  • TMQ 2,3,5-trimethylquinone
  • TMP 2,3,6-trimethylphenol
  • EP 0694541 A1 discloses that alkylene carbonates are very suitable for the condensation process of TMHQ and isophytol.
  • Cyclic alkyl carbonates are, somehow, still unusual solvents for chemical reactions, the more and more, however, these solvents are used due to excellent ecotoxicity and positive fire and working hazard properties.
  • alkylene carbonates have a flashpoint of more than 120°C. In contrast to this, this is not the case for non-cyclic carbonates (such as dimethyl carbonate or diethylcarbonate (flashpoint: 14°C resp. 25°C)).
  • flashpoint such as dimethyl carbonate or diethylcarbonate (flashpoint: 14°C resp. 25°C)).
  • alkylene carbonates are attractive in view of cost.
  • alkylene carbonates which is well-known to those skilled in the art, are prone to hydrolysis.
  • the hydrolysis leads to formation of CO2 and the respective alkanediol.
  • phenol and alkylene carbonates form different alkanediol ethers of the phenols.
  • the problem to be solved by the present invention is to offer a process for the manufacturing of a-tocopherol from TMP via TMQ, which uses for all reaction steps the same solvent.
  • a “C x-y -alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms.
  • the alkyl group can be linear or branched.
  • -CFI(CFl3)-CFl2-CFl3 is considered as a C4-alkyl group.
  • butyl can be "n-butyl” or “/so-butyl” or "sec-butyl” or "tert- butyl”.
  • a “C x -y-alkane” accordingly corresponds to a linear or branched alkane comprising x to y carbon atoms.
  • the term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.
  • substituents, moieties, or groups that designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.
  • the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label.
  • the solvent of the formula (X) used in the three steps a) and b) and c) is the same molecule (i.e. the groups Y 1 and Y 2 have the same meaning for the steps a) and b) and c).
  • inert means that under the conditions of the reaction said material does not undergo any chemical reaction.
  • the process comprises a step a) a) oxidation of a compound of the formula (II) to yield a compound of the formula (III).
  • the oxidation is performed by a suitable oxidizing agent (Ox).
  • oxidizing agent is O2 or peroxides, particularly in the form of H2O2, hydroperoxides, peroxy acids and esters of peroxy acids, in the presence of a catalyst.
  • the oxidation in step a) is performed using an oxidizing agent which is either oxygen or hydrogen peroxide, more preferred oxygen, in the presence of a catalyst.
  • the oxidation is performed in the presence of catalyst being a salt or complex of a transition metal which is selected from the group consisting of Ce, Mn, Fe, Cu and Zn, particularly is selected from the group consisting of Mn, Fe, Cu and Zn, more preferably of Mn(ll), Mn(IV), Fe(ll), Fe(lll), Cu(l), Cu(ll) or Zn(ll).
  • catalyst being a salt or complex of a transition metal which is selected from the group consisting of Ce, Mn, Fe, Cu and Zn, particularly is selected from the group consisting of Mn, Fe, Cu and Zn, more preferably of Mn(ll), Mn(IV), Fe(ll), Fe(lll), Cu(l), Cu(ll) or Zn(ll).
  • the oxidation is preferably performed in the presence of at least one Cu(l) salt and/or at least one Cu(ll) salt, more preferred at least one Cu(ll) salt.
  • the Cu(ll) salts are particularly copper halides. Most preferred is
  • Step a) is usually carried out at a temperature of from 40°C to 95°C, particularly between 50°C and 85°C, preferably between 55°C and 80°C.
  • the above process is preferably carried out in the presence of an organic acid.
  • the organic acid is selected from the group consisting of acetic acid, adipic acid, lactic acid, oxalic acid, citric acid, particularly acetic acid.
  • the amount of organic acid added is in an amount that the pH of the reaction mixture is in the range of 4.8 -6.8, particularly 5 - 6.8, preferably 5.5 - 6.2.
  • the amounts of organic acid added is 0.15 - 3.5 mol- equivalent, preferably 1.5 -2.5 mol-equivalent, based on the amount of compound of formula (II). It is important to stress that the optional organic acid is used in small amounts only. This is very advantageous as in view of handling, particularly in view of flammability.
  • the state-of-the-art technology uses large amounts of highly volatile organic substances, such as solvents or organic acids, in the presence of oxygen or oxygen-containing gas mixtures.
  • the oxidation takes place at a pH of 5 - 7.8, particularly of 5.5 - 6.8.
  • molecular oxygen (O2) can be used as oxidizing agent.
  • a mixture comprising oxygen and an inert gas is used as oxidizing agent. It is preferred that the amount of oxygen in such a mixture comprising oxygen and an inert gas is at least 15 % by volume, particularly at least 20 % by volume.
  • Such a mixture may, for example, be a binary mixture such as a mixture oxygen/nitrogen or oxygen/argon or alike.
  • Said mixture can consist of or comprise two or more inert gases. It is particularly preferred to use air as such a mixture comprising oxygen and an inert gas.
  • the oxidizing agent is O2 in the form of air or pure oxygen. Most preferred the oxidizing agent is O2 in the form of pure oxygen.
  • the process comprises a step b) which follows the step a) b) reduction of the compound of the formula (III) to yield the compound of the formula (I).
  • the compound of the formula (III) is reduced in the above process to the compound of the formula (I) by a reducing agent ⁇ Red).
  • the reducing agent is molecular hydrogen.
  • the compound of the formula (III) is hydrogenated by molecular hydrogen in the presence of a metal catalyst.
  • the metal of the metal catalyst is preferably selected from the group consisting of Ni, Ir, Pd, Pt, Rh and Ru, particularly Pd or Pt, particularly a heterogeneous metal catalyst on a carrier or a support material.
  • the metal catalyst can be a catalyst comprising more than one of the mentioned metals.
  • the metal of the metal catalyst is palladium.
  • the metal catalyst is preferably a heterogeneous metal catalyst on a carrier or a support material.
  • Such carrier material is particularly a solid material having a high surface area, to which the metal is affixed.
  • the support may be inert or participate in the catalytic reactions.
  • Typical supports/carrier material include various kinds of carbon or an oxide of Si, Al, Ce, Ti or Zr, particularly of Al or Si, such as alumina or silica.
  • the preferred support/carrier material is carbon. ln case the support is Cer, the preferred oxide is CeCte.
  • the oxide of Al is AI 2 O 3 and AIO(OH). Particularly preferred is Boehmite.
  • the surface area of the carrier is preferably in the range of 800 to 1500 m 2 /g, particularly of 1000 to 1200 m 2 /g.
  • the heterogeneous metal catalyst may also be affixed or immobilized on a surface of a larger object typically in form of a structured packing element which might be a part of the reactor in which the reduction takes place or an element which is inserted into said reactor.
  • the support material is, hence, preferably a structured packing element.
  • This structured packing element may be a dumped packing, a knit, an open-celled foam structure, preferably made of plastic, for example polyurethane or melamine resin, or ceramic, or a structured packing element, as already known in principle, i.e. by its geometric shape, from distillation and extraction technology.
  • structured packings in principle have a substantially smaller hydraulic diameter, frequently by a factor of from 2 to 10, than comparable internals in the field of distillation and extraction technology.
  • Useful structured packing elements are in particular metal fabric packings and wire fabric packings, for example of the design Montz A3, Sulzer BX, DX and EX. Instead of metal fabric packings, it is also possible to use structured packings made of other woven, knitted or felted materials.
  • structured packings are of flat or corrugated sheets, preferably without perforation, or other relatively large orifices, for example corresponding to the designs Montz Bl or Sulzer Mellapak.
  • the structured packings made of expanded metal are also advantageous, for example structured packings of the type Montz BSH.
  • the metal catalyst is a palladium catalyst, particularly a palladium on carbon catalyst (Pd/C).
  • the catalytic metal loading (weight ratio metal/catalyst, i.e. the weight metal / weight (metal+carrier)) is typically between 1 to 20%, preferably between 4 and 11 %, more preferably between 4 and 6% by weight.
  • the reducing agent is a transfer hydrogenation agent.
  • the compound of the formula (III) is transfer hydrogenated by a transfer hydrogenation agent to yield the compound of the formula (I).
  • Said transfer hydrogenation agent is preferably formic acid and/or a formic acid salt.
  • the reducing agent is a dithionite salt.
  • the reduction can be achieved with sodium dithionite in water according to the method as disclosed by K. Sato, Y. Fujima, A. Yamada Bull. Chem. Soc. Jap. 1968, 41, 442-444, the entire content of which is hereby incorporated by reference.
  • the reducing agent is either molecular hydrogen or a transfer hydrogenation agent or a dithionite salt.
  • Q represents a halide
  • Q represents Cl.
  • the acyloxy is preferably a group of the formula wherein R 10 represents either an C-i- 6 -alkyl or an aryl group, which is optionally substituted, particularly by at least one Ci- 6 -alkyl group.
  • R 10 represents either an Ci- 6 -alkyl or to a phenyl group.
  • R 10 represents either a methyl or a phenyl group, most preferably a methyl group.
  • Particular examples for compounds of formula (IV-A) are isophytol, isophytyl chloride, isophytyl bromide, isophytyl iodide, isophytyl acetate, isophytyl methanesulfonate, isophytyl ethanesulfonate, isophytyl benzenesulfonate, and isophytyl toluenesulfonate.
  • Particular examples for compounds of formula (IV-B) are phytol, phytyl chloride, phytyl bromide, phytyl iodide, phytyl acetate, phytyl methanesulfonate, phytyl ethanesulfonate, phytyl benzenesulfonate, and phytyl toluenesulfonate.
  • the compound of formula (IV-B) can be used as E/Z-mixture as well as in pure E- or pure Z-form. Preferred is their use as E/Z-mixtures.
  • Q represents preferably OH or Cl.
  • preferred as compound of formula (IV-A) or (IV-B) are phytol, isophytol, phytyl chloride or isophytyl chloride, more preferred phytol or isophytol. Most preferred is isophytol.
  • the use of compounds of formula (IV-A) are preferred over compounds of formula (IV-B).
  • step c) the condensation reaction of step c) can be performed as described for example in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, 7 th Edition, “Vitamins”, page 44 - 46.
  • This condensation reaction (step c)) is preferably performed using a Lewis or a Bnzsnsted acid.
  • Said Lewis or a Bnzsnsted acid are particularly those as mentioned in
  • a key element of the present invention is the solvent of formula (X).
  • All reaction steps a) and b) and c) are performed in at least one solvent of the formula (X) wherein Y 1 and Y 2 represent independently from each other either H or a methyl or ethyl group; or in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of the formula (X) and at least one solvent (B) which is not miscible with solvent of the formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1 .
  • the substituent Y 1 is preferably H.
  • ethylene carbonate is a preferred solvent of the formula (X).
  • propylene carbonate is another preferred solvent of the formula (X).
  • butylene carbonate is another preferred solvent of the formula (X).
  • Ethylene carbonate and propylene carbonate are the most preferred solvents of the formula (X).
  • all three reaction steps a) and b) and c) are performed in at least two solvents of the formula (X), particularly a binary or ternary mixture of ethylene carbonate and/or propylene carbonate and/or butylene carbonate, most preferably a binary mixture of ethylene carbonate and propylene carbonate. It is preferred that the ratio of ethylene carbonate to propylene carbonate is between 20:80 to 80:20, particularly 25:75 to 75:25.
  • the solvent of the formula is a carbonate solvent as commer cialized by Huntsman under the trademark Jeffsol®, particularly the blends of ethylene carbonate with propylene carbonate Jeffsol® EC-75, Jeffsol® EC-50 and Jeffsol® EC-25.
  • Jeffsol® a carbonate solvent as commer cialized by Huntsman under the trademark Jeffsol®, particularly the blends of ethylene carbonate with propylene carbonate Jeffsol® EC-75, Jeffsol® EC-50 and Jeffsol® EC-25.
  • reaction steps a) and/or b) and/or c) are performed in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of the formula (X) and at least one solvent (B) which is not miscible with solvent of the formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1.
  • the solvent (B) which is not miscible with the solvent (A) of the formula (X) is preferably a hydrocarbon, more preferably an alkane, particularly a C5-16- alkane, most particularly a C 6-8 -alkane. Most preferably the solvent (B) is either hexane or heptane.
  • the a-tocopherol of formula (V) is accumulated in the solvent (B) which is not miscible with the solvent (A).
  • the good solubility also allows that the process can be performed at low temperatures, particularly at temperatures below 70 °C, more preferably at temperatures between the melting point of the solvent of the formula (X) and 60°C.
  • the solvent of formula (X) has an excellent stability against the oxidizing agent, particularly against molecular oxygen as well against the reducing agent. And the yield for both reaction step is high.
  • the catalyst can be easily removed from the reaction mixture.
  • Particularly useful for this separation are either filtration or extraction.
  • Alkylene carbonates are very attractive solvents due to their excellent ecotoxicity and positive fire and working hazard properties as well as in view of cost.
  • Figure 1 shows an overview of the complete reaction scheme for the manufacturing of a-tocopherol from TMP via TMQ via TMHQ in the alkylene carbonate of formula (X).
  • the invention relates to the use of ethylene carbonate and/or propylene carbonate and/or butylene carbonate as a solvent for the reduction of 2,3,5-trimethyM ,4-benzoquinone to 2,3,5-trimethyl- hydroquinone.
  • TMQ 2,3,5-trimethylquinone
  • TMHQ 2,3,5-trimethylhydro- quinone

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to the formation of α-tocopherol from 2,3,6- tri¬methyl¬phenol comprising the steps a) the oxidation of 2,3,6-trimethylphenol to 2,3,5-trimethylquinone. b) the reduction of 2,3,5-trimethylquinone to 2,3,5-trimethylhydroquinone c) the condensation of 2,3,5-trimethylhydroquinone and isophytol or a phytol derivative in such a manner that all reaction steps a), b) and c) are performed in cyclic alkylene carbonate solvent.

Description

FORMATION OF ALPHA TOCOPHEROL FROM 2,3,6-TRIMETHYLPHENOL
Technical Field
The present invention relates to the field of the synthesis of a-tocopherol.
Background of the invention a-Tocopherol is an important substance and is part of vitamin E.
The major reaction pathway in its chemical synthesis uses a condensation of (iso)phytol with 2,3,5-trimethylhydroquinone (TMHQ) as disclosed for example in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, 7th Edition, “Vitamins”, page 44 -46.
TMHQ is typically produced by reduction of 2,3,5-trimethylquinone (TMQ), which can be obtained by oxidation of 2,3,6-trimethylphenol (=TMP). When using copper chloride typically undesired chlorinated side products of TMP are observed in the known processes.
This reaction sequence, however, involves different solvent systems. As the staring material and the products of each these reaction steps have different solubilities, very often precipitation or solubility problems are present for each step when using a solvent. Low solubility and precipitations negatively impact the yield, and the purity of the product of respective reaction step. Furthermore, precipitation often leads often to incrustation which increase cost for maintenance of the reaction equipment as well as for the recycling of chemicals, particularly of catalysts.
As such precipitation or solubility problems are present, typically a specific (different) solvent is used for each of these steps and/or very high temperatures need to be applied to increase solubility.
EP 0694541 A1 discloses that alkylene carbonates are very suitable for the condensation process of TMHQ and isophytol.
Cyclic alkyl carbonates (=alkylene carbonates) are, somehow, still unusual solvents for chemical reactions, the more and more, however, these solvents are used due to excellent ecotoxicity and positive fire and working hazard properties. For examples alkylene carbonates have a flashpoint of more than 120°C. In contrast to this, this is not the case for non-cyclic carbonates (such as dimethyl carbonate or diethylcarbonate (flashpoint: 14°C resp. 25°C)). Finally, alkylene carbonates are attractive in view of cost.
However, as discussed in US 2003/0060383 A1, an unfortunate property of alkylene carbonates which is well-known to those skilled in the art, is that these compounds are prone to hydrolysis. The hydrolysis leads to formation of CO2 and the respective alkanediol. Furthermore, it is also known to the person skilled in the art, for example from P. Ziosi et al. , Catal. Sci. Technol. 2014, 4, 4386-4395, that phenol and alkylene carbonates form different alkanediol ethers of the phenols.
Summary of the invention
Therefore, the problem to be solved by the present invention is to offer a process for the manufacturing of a-tocopherol from TMP via TMQ, which uses for all reaction steps the same solvent.
It has been, surprisingly, found that a process according to claim 1 is able to solve this problem.
It has been particularly found that the alkylene carbonates of formula (X) are optimally suited for this purpose. Not only remarkably high yields for all reaction steps a) and b) and c) have been found, it has also been observed no indication of any degradation of the solvent during all reaction steps.
Due to the good solubility of TMP, TMQ and TMHQ the synthesis can be performed at moderate temperatures, which reduce the formation of side or degradation products. Particularly precipitation of the products and intermediates is avoided, which heavily reduces the labor, invoked by removal of undesired incrustations in the production equipment.
Particularly advantageous in the present process is that the use of different reaction solvents for the subsequent steps can be avoided, which results in less cost for storage equipment (such as additional tanks), less cost for handling of reaction mixtures and less cost for recycling of solvents. Finally, any removal of solvents necessary in the state-of-the-art processes results in additional cost in time and energy used for such operations such as distillation which can be saved in the present process.
Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims. Detailed description of the invention
In a first aspect the present invention relates to a process for the manufacturing the compound of the formula (V) comprising the reaction step a) followed by reaction step b) and followed by step c) a) oxidation of a compound of the formula (II) to yield a compound of the formula (III); b) reduction of the compound of the formula (III) to yield a compound of the formula (I) c) condensation of the compound of the formula (I) with compounds of the formula (IV-A) or (IV-B) wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, particularly acetoxy or benzoyloxy, methane- sulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); wherein any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E-configuration; to yield the compound of the formula (V) characterized in that all reaction steps a) and b) and c) are performed in at least one solvent of the formula (X) wherein Y1 and Y2 represent independently from each other either H or a methyl or ethyl group; or in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of formula (X) and at least one solvent (B) which is not miscible with solvent of formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1.
For sake of clarity, some terms as been used in the present document are defined as follows:
In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CFI(CFl3)-CFl2-CFl3 is considered as a C4-alkyl group. Flence, "propyl" can be "n-propyl" or "/so- propyl" (=isopropyl). Analogously, "butyl" can be "n-butyl" or "/so-butyl" or "sec-butyl" or "tert- butyl".
A “Cx-y-alkane” accordingly corresponds to a linear or branched alkane comprising x to y carbon atoms. The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule. In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label.
As a consequence, for clarification, the solvent of the formula (X) used in the three steps a) and b) and c) is the same molecule (i.e. the groups Y1 and Y2 have the same meaning for the steps a) and b) and c).
The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.
The term “inert”, as used in this document in describing a material, means that under the conditions of the reaction said material does not undergo any chemical reaction.
Step a) oxidation
The process comprises a step a) a) oxidation of a compound of the formula (II) to yield a compound of the formula (III). The compound of formula (II), 2,3,6-trimethylphenol (=TMP), is known to the person skilled in the art. The oxidation is performed by a suitable oxidizing agent (Ox). Particularly suitable as oxidizing agent is O2 or peroxides, particularly in the form of H2O2, hydroperoxides, peroxy acids and esters of peroxy acids, in the presence of a catalyst.
It is preferred that the oxidation in step a) is performed using an oxidizing agent which is either oxygen or hydrogen peroxide, more preferred oxygen, in the presence of a catalyst.
Particularly the oxidation is performed in the presence of catalyst being a salt or complex of a transition metal which is selected from the group consisting of Ce, Mn, Fe, Cu and Zn, particularly is selected from the group consisting of Mn, Fe, Cu and Zn, more preferably of Mn(ll), Mn(IV), Fe(ll), Fe(lll), Cu(l), Cu(ll) or Zn(ll). Particularly the oxidation is preferably performed in the presence of at least one Cu(l) salt and/or at least one Cu(ll) salt, more preferred at least one Cu(ll) salt. The Cu(ll) salts are particularly copper halides. Most preferred is CuCl2(this salt is typically used in the form of its hydrate CuC ^FhO).
Surprisingly, it has been found that the formation of chlorinated TMP, i.e. 4-chloro-2,3,6-trimethylphenol, which is a known undesired side product, can be avoided when using the solvent of formula (X).
Step a) is usually carried out at a temperature of from 40°C to 95°C, particularly between 50°C and 85°C, preferably between 55°C and 80°C.
The above process is preferably carried out in the presence of an organic acid. Preferably, the organic acid is selected from the group consisting of acetic acid, adipic acid, lactic acid, oxalic acid, citric acid, particularly acetic acid.
The amount of organic acid added is in an amount that the pH of the reaction mixture is in the range of 4.8 -6.8, particularly 5 - 6.8, preferably 5.5 - 6.2.
It is preferred that the amounts of organic acid added is 0.15 - 3.5 mol- equivalent, preferably 1.5 -2.5 mol-equivalent, based on the amount of compound of formula (II). It is important to stress that the optional organic acid is used in small amounts only. This is very advantageous as in view of handling, particularly in view of flammability. The state-of-the-art technology, however, uses large amounts of highly volatile organic substances, such as solvents or organic acids, in the presence of oxygen or oxygen-containing gas mixtures.
Furthermore, when the reaction would be made under strongly acid condition, major quantities of base would be needed when neutralizing the residues after termination of the reaction, which would be, therefore also very disadvantageous from an economic and/or environmental point of view. With the present invention, it has been observed that the reaction excellently proceeds also at conditions at slightly acidic pH.
Therefore, it is preferred that the oxidation takes place at a pH of 5 - 7.8, particularly of 5.5 - 6.8.
In one embodiment, molecular oxygen (O2) can be used as oxidizing agent. In another embodiment, a mixture comprising oxygen and an inert gas is used as oxidizing agent. It is preferred that the amount of oxygen in such a mixture comprising oxygen and an inert gas is at least 15 % by volume, particularly at least 20 % by volume. Such a mixture may, for example, be a binary mixture such as a mixture oxygen/nitrogen or oxygen/argon or alike. Said mixture can consist of or comprise two or more inert gases. It is particularly preferred to use air as such a mixture comprising oxygen and an inert gas.
It is preferred that that the oxidizing agent is O2 in the form of air or pure oxygen. Most preferred the oxidizing agent is O2 in the form of pure oxygen.
Oxygen and particularly air are very cheap oxidizing agents.
The conditions for the oxidation step are, principally, known to the person skilled in the art. If desired the reaction mixture after the step a) can be worked up, particularly extracted. Step b) reduction
The process comprises a step b) which follows the step a) b) reduction of the compound of the formula (III) to yield the compound of the formula (I).
The compound of the formula (III) is reduced in the above process to the compound of the formula (I) by a reducing agent {Red).
In one preferred embodiment of the invention the reducing agent is molecular hydrogen. In other words, in one embodiment the compound of the formula (III) is hydrogenated by molecular hydrogen in the presence of a metal catalyst.
The metal of the metal catalyst is preferably selected from the group consisting of Ni, Ir, Pd, Pt, Rh and Ru, particularly Pd or Pt, particularly a heterogeneous metal catalyst on a carrier or a support material. The metal catalyst can be a catalyst comprising more than one of the mentioned metals.
It is preferred that the metal of the metal catalyst is palladium.
The metal catalyst is preferably a heterogeneous metal catalyst on a carrier or a support material.
Such carrier material is particularly a solid material having a high surface area, to which the metal is affixed. The support may be inert or participate in the catalytic reactions.
Typical supports/carrier material include various kinds of carbon or an oxide of Si, Al, Ce, Ti or Zr, particularly of Al or Si, such as alumina or silica. The preferred support/carrier material is carbon. ln case the support is Cer, the preferred oxide is CeCte. Preferably, the oxide of Al is AI2O3 and AIO(OH). Particularly preferred is Boehmite.
The surface area of the carrier is preferably in the range of 800 to 1500 m2/g, particularly of 1000 to 1200 m2/g.
The heterogeneous metal catalyst may also be affixed or immobilized on a surface of a larger object typically in form of a structured packing element which might be a part of the reactor in which the reduction takes place or an element which is inserted into said reactor. The support material is, hence, preferably a structured packing element.
This structured packing element may be a dumped packing, a knit, an open-celled foam structure, preferably made of plastic, for example polyurethane or melamine resin, or ceramic, or a structured packing element, as already known in principle, i.e. by its geometric shape, from distillation and extraction technology. However, for the purposes of the present invention, structured packings in principle have a substantially smaller hydraulic diameter, frequently by a factor of from 2 to 10, than comparable internals in the field of distillation and extraction technology. Useful structured packing elements are in particular metal fabric packings and wire fabric packings, for example of the design Montz A3, Sulzer BX, DX and EX. Instead of metal fabric packings, it is also possible to use structured packings made of other woven, knitted or felted materials. Further useful structured packings are of flat or corrugated sheets, preferably without perforation, or other relatively large orifices, for example corresponding to the designs Montz Bl or Sulzer Mellapak. The structured packings made of expanded metal are also advantageous, for example structured packings of the type Montz BSH.
It is preferred that the metal catalyst is a palladium catalyst, particularly a palladium on carbon catalyst (Pd/C).
The catalytic metal loading (weight ratio metal/catalyst, i.e. the weight metal / weight (metal+carrier)) is typically between 1 to 20%, preferably between 4 and 11 %, more preferably between 4 and 6% by weight. A very preferred hetero geneous metal catalyst is palladium on carbon catalyst (Pd/C) of which 5 % by weight is palladium (i.e. loading = 5%). In another preferred embodiment of the invention the reducing agent is a transfer hydrogenation agent. In other words, in another embodiment the compound of the formula (III) is transfer hydrogenated by a transfer hydrogenation agent to yield the compound of the formula (I). Said transfer hydrogenation agent is preferably formic acid and/or a formic acid salt.
In an even further preferred embodiment of the invention the reducing agent is a dithionite salt. The reduction can be achieved with sodium dithionite in water according to the method as disclosed by K. Sato, Y. Fujima, A. Yamada Bull. Chem. Soc. Jap. 1968, 41, 442-444, the entire content of which is hereby incorporated by reference.
Hence, preferably the reducing agent is either molecular hydrogen or a transfer hydrogenation agent or a dithionite salt.
Step c) condensation
The process comprises a step c) which follows step b): c) condensation of the compound of the formula (I) with compounds of the formula (IV-A) or (IV-B) wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, particularly acetoxy or benzoyloxy, methane- sulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); wherein any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E-configuration; to yield the compound of the formula (V) In case Q represents a halide, preferably Q represents Cl.
In case Q represents an acyloxy the acyloxy is preferably a group of the formula wherein R10 represents either an C-i-6-alkyl or an aryl group, which is optionally substituted, particularly by at least one Ci-6-alkyl group.
Preferably R10 represents either an Ci-6-alkyl or to a phenyl group.
More preferably, R10 represents either a methyl or a phenyl group, most preferably a methyl group.
Particular examples for compounds of formula (IV-A) are isophytol, isophytyl chloride, isophytyl bromide, isophytyl iodide, isophytyl acetate, isophytyl methanesulfonate, isophytyl ethanesulfonate, isophytyl benzenesulfonate, and isophytyl toluenesulfonate.
Particular examples for compounds of formula (IV-B) are phytol, phytyl chloride, phytyl bromide, phytyl iodide, phytyl acetate, phytyl methanesulfonate, phytyl ethanesulfonate, phytyl benzenesulfonate, and phytyl toluenesulfonate. The compound of formula (IV-B) can be used as E/Z-mixture as well as in pure E- or pure Z-form. Preferred is their use as E/Z-mixtures.
Q represents preferably OH or Cl.
Hence, preferred as compound of formula (IV-A) or (IV-B) are phytol, isophytol, phytyl chloride or isophytyl chloride, more preferred phytol or isophytol. Most preferred is isophytol. The use of compounds of formula (IV-A) are preferred over compounds of formula (IV-B).
It has been found that the condensation reaction of step c) can be performed as described for example in Ullmann's Encyclopedia of Industrial Chemistry, Release 2010, 7th Edition, “Vitamins”, page 44 - 46.
This condensation reaction (step c)) is preferably performed using a Lewis or a Bnzsnsted acid. Said Lewis or a Bnzsnsted acid are particularly those as mentioned in
EP 0949255 A1 and Bonrath et al. , Adv. Synth. Catal. 2002, 344 37-39.
Solvent of the formula (X)
A key element of the present invention is the solvent of formula (X).
All reaction steps a) and b) and c) are performed in at least one solvent of the formula (X) wherein Y1 and Y2 represent independently from each other either H or a methyl or ethyl group; or in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of the formula (X) and at least one solvent (B) which is not miscible with solvent of the formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1 .
The substituent Y1 is preferably H.
In a preferred embodiment, Y1 = Y2 = H. Hence, ethylene carbonate is a preferred solvent of the formula (X). In a further preferred embodiment, Y1 = H and Y2 = Chh. Hence, propylene carbonate is another preferred solvent of the formula (X).
In a further preferred embodiment, Y1 = H and Y2 = CH2CH3. Hence, butylene carbonate is another preferred solvent of the formula (X).
Ethylene carbonate and propylene carbonate are the most preferred solvents of the formula (X).
In a very preferred embodiment, all three reaction steps a) and b) and c) are performed in at least two solvents of the formula (X), particularly a binary or ternary mixture of ethylene carbonate and/or propylene carbonate and/or butylene carbonate, most preferably a binary mixture of ethylene carbonate and propylene carbonate. It is preferred that the ratio of ethylene carbonate to propylene carbonate is between 20:80 to 80:20, particularly 25:75 to 75:25.
Preferably, the solvent of the formula is a carbonate solvent as commer cialized by Huntsman under the trademark Jeffsol®, particularly the blends of ethylene carbonate with propylene carbonate Jeffsol® EC-75, Jeffsol® EC-50 and Jeffsol® EC-25.
In a further embodiment, the reaction steps a) and/or b) and/or c) are performed in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of the formula (X) and at least one solvent (B) which is not miscible with solvent of the formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1.
The solvent (B) which is not miscible with the solvent (A) of the formula (X) is preferably a hydrocarbon, more preferably an alkane, particularly a C5-16- alkane, most particularly a C6-8-alkane. Most preferably the solvent (B) is either hexane or heptane.
It has been shown that the above process allows to oxidize TMP to TMQ as well as to reduce TMQ to TMHQ as well as to condense TMHQ with the isophytol or phytol derivative of formula (IV-A) or (IV-B) in an efficient way to the compound of the formula (V). The use of the solvent of formula (X) is very advantageous as the starting material for all three processes steps, i.e. the compound of formula (II), respectively of formula (III), as well as the compound of the formula (I) are well soluble and no precipitation occurs. The product of condensation, a-tocopherol, i.e. compound of formula (V), typically separates from the phase of solvent of formula (X) on cooling of the reaction mixture or can be easily extracted by use of a suitable aliphatic or aromatic hydrocarbon, such as hexane.
In case where the process is performed in a two-phase solvent mixture, the a-tocopherol of formula (V) is accumulated in the solvent (B) which is not miscible with the solvent (A).
The good solubility also allows that the process can be performed at low temperatures, particularly at temperatures below 70 °C, more preferably at temperatures between the melting point of the solvent of the formula (X) and 60°C.
The solubility of hydrogen in the solvent of formula (X) is very high, allowing a good yield and selectivity.
The solvent of formula (X) has an excellent stability against the oxidizing agent, particularly against molecular oxygen as well against the reducing agent. And the yield for both reaction step is high.
It has been shown that the solvent of formula (X) is also very stable against the reaction conditions of the condensation step c).
It has been surprisingly not observed that the solvent is decomposed into the respective diol and CO2. Furthermore, no formation of ethers between the respective diol and the phenol of the formula (I) have been observed.
After the end of the reaction, the catalyst can be easily removed from the reaction mixture. Particularly useful for this separation are either filtration or extraction.
It is very advantageous that all three steps a) and b) and c) can be prepared in one solvent medium. The fact that no change of solvent needs to be made during the whole process starting from (poly) alkylphenol to tocopherol is very advantageous in view of cost, particularly in view of reduced labor and reducing of production process complexity. Changes of solvents always lead to additional working steps, problems with logistics and recovery or disposal of waste.
Alkylene carbonates are very attractive solvents due to their excellent ecotoxicity and positive fire and working hazard properties as well as in view of cost.
Figure 1 shows an overview of the complete reaction scheme for the manufacturing of a-tocopherol from TMP via TMQ via TMHQ in the alkylene carbonate of formula (X).
Therefore, in a further embodiment, the invention relates to the use of ethylene carbonate and/or propylene carbonate and/or butylene carbonate as a solvent for the reduction of 2,3,5-trimethyM ,4-benzoquinone to 2,3,5-trimethyl- hydroquinone.
Examples The present invention is further illustrated by the following experiments.
Oxidation of TMP
7.5 g CuC ^PhO, and the respective solvent have been added into the reactor, then 5.9 g melted 2,3,6-trimethylphenol has been added slowly (60 minutes) under stirring with a KBG-stirrer with teflon blade at 80°C and under flowing oxygen (1 Nml/min at a pressure of 1.25 bar). After the TMP has been added stirring continued for another 30 minutes.
The product, i.e. 2,3,5-trimethylquinone (TMQ), has been isolated from the reaction mixture in a yield as given in table 1, and characterized.
The amounts of 4-chloro-2,3,6-trimethylphenol = "CI-TMP" has been determined by GC. The amounts of ethylene glycol have been identified by HPLC with a refraction index detector.
Table 1. Oxidation of TMP to TMQ in different solvents. The results of table 1 show that the oxidation in the carbonate can be performed in similarly high yields as in other solvents. However, in the oxidation in carbonates no chlorinated side products (such as CI-TMP) have been found. Also no formation of ethylene glycol has been observed.
Reduction of TMQ
30.24 g (200 mmol) of 2,3,5-trimethylquinone (TMQ) dissolved in 122 g of the warm solvent as given in table 2 have been added to a 350 ml 4-neck glass flask. 0.048 mol % (0.0934 mmol) Pd/C hydrogenation catalyst (5% metal loading) have been added. After inertisation with nitrogen (3 rinsing/evacuation cycles) molecular hydrogen has been added and heated to 80°C under stirring. After 30 minutes no hydrogen was consumed anymore. The reaction was stirred for another 30 minutes at this temperature.
After removal of the catalyst, a clear solution CS was obtained without any precipitation. From this solution the formed product, i.e. 2,3,5-trimethylhydro- quinone (TMHQ), can be isolated. Such isolation by extraction show a very high yield.
Condensation of TMHQ with isophvtol To the solutions CS of TMHQ as prepared above, 120 ml n-heptane and
0.052 mol % heteropolytungstic acid was added and 100 mol of isophytol was added under intense stirring during 30 minutes at reflux temperature The product, i.e. a-tocopherol (TC), has been isolated from the heptane phase in a yield as given in table 3, and characterized.
Table 3: Condensation of TMHQ to TC.

Claims

Claims
1. A process for the manufacturing the compound of the formula (V) comprising the reaction step a) followed by reaction step b) and followed by step c) a) oxidation of a compound of the formula (II) to yield a compound of the formula (III); b) reduction of the compound of the formula (III) to yield a compound of the formula (I) c) condensation of the compound of the formula (I) with compounds of the formula (IV-A) or (IV-B) wherein Q is a substituent selected from the group consisting of OH, halide, acyloxy, particularly acetoxy or benzoyloxy, methane- sulfonyloxy (=mesyloxy), ethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy (=tosyloxy); wherein any wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z- or in the E-configuration; to yield the compound of the formula (V) characterized in that all reaction steps a) and b) and c) are performed in at least one solvent of the formula (X) wherein Y1 and Y2 represent independently from each other either H or a methyl or ethyl group; or in a two-phase solvent mixture comprising at least one solvent (A) being of a solvent of formula (X) and at least one solvent (B) which is not miscible with solvent of formula (X) at room temperature in a volume ratio of (A)/(B) of between 1/50 and 50/1.
2. The process according to claim 1, characterized in that Y1 = Y2 = H.
3. The process according to claim 1, characterized in that Y1 = H and Y2 = Chh.
4. The process according to claim 1 , characterized in that the reaction steps a) and/or b) and/or c) are performed in a solvent mixture of a solvent (A) of formula (X) and a solvent (B) being a hydrocarbon, preferably an alkane, more preferably a Cs-16-alkane, particularly a Ce-8-alkane.
5. The process according to anyone of the preceding claims, characterized in that all reaction steps a) and b) and c) are performed in a solvent mixture of at least two solvents of formula (X), particularly in a mixture of ethylene carbonate and propylene carbonate.
6. The process according to anyone of the preceding claims characterized in that the oxidation in step a) is performed using an oxidizing agent which is either oxygen or hydrogen peroxide, in the presence of a catalyst.
7. The process according to anyone of the preceding claims characterized in that the reduction in step b) is performed using a reducing agent which is either molecular hydrogen or a transfer hydrogenation agent or a dithionite salt.
8. The process according to anyone of the preceding claims characterized in that the reduction in step b) is performed using a reducing agent which is molecular hydrogen in the presence of a heterogeneous metal catalyst wherein the metal is selected from the group consisting of Ni, Ir, Pd, Pt, Rh and Ru, particularly Pd or Pt, on a carrier or a support material.
9. The process according to claim 8, characterized in that the carrier is a carbon or an oxide of Si, Al, Ce, Ti or Zr, particularly of Al or Si, preferably carbon.
10. The process according to anyone of the preceding claims claim 8 to 10, characterized in that the surface area of the carrier is in the range of 800 to 1500 m2/g, particularly of 1000 to 1200 m2/g.
11. The process according to claim 8, characterized in that the support material is a structured packing element.
12. The process according to anyone of the preceding claims characterized in that the condensation step in step c) is performed using a Lewis or a Bnzsnsted acid.
13. Use of ethylene carbonate and/or propylene carbonate and/or butylene carbonate as a solvent for the reduction of 2,3,5-thmethyM ,4-benzoquinone to 2,3,5-trimethylhydroquinone.
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