WO2017098050A1 - Process for the manufacture of 6,10,14-trimethylpentadecan-2-one, isophytol and alpha-tocopherol - Google Patents

Process for the manufacture of 6,10,14-trimethylpentadecan-2-one, isophytol and alpha-tocopherol Download PDF

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WO2017098050A1
WO2017098050A1 PCT/EP2016/080664 EP2016080664W WO2017098050A1 WO 2017098050 A1 WO2017098050 A1 WO 2017098050A1 EP 2016080664 W EP2016080664 W EP 2016080664W WO 2017098050 A1 WO2017098050 A1 WO 2017098050A1
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dehydrofarnesylacetone
range
process according
catalyst
mixtures
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PCT/EP2016/080664
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French (fr)
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Werner Bonrath
Jonathan Alan Medlock
Peter Hans RIEBEL
Rene Tobias Stemmler
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Dsm Ip Assets B.V.
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Publication of WO2017098050A1 publication Critical patent/WO2017098050A1/en

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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds

Definitions

  • the present invention is directed to a process for the manufacture of 6, 10, 1 -trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds (see Fig. 3).
  • the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof. Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.
  • (2E,6E)-Farnesal can be obtained by selective oxidation of (2E,6E)-farnesol (see Fig. 1 ), e.g. by the use of manganese oxide in a solvent with only a small change in the carbon-carbon double bond geometry.
  • oxygen and palladium catalysts as described in Kakiuchi et al, Bull Chem Soc Jpn, 2001 , 165-172 (especially page 168, Table 3, example 11 ) may be used for the selective oxidation of (2E,6E)-farnesol to (2E,6E)-farnesal. This selective oxidation is also an embodiment of the present invention.
  • the (2E,6E)-farnesol may itself be extracted from natural sources or obtained by fermentation or synthesized synthetically and, if needed, separated from (2Z,6E)-, (2E,6Z)- and (2Z,6Z)-farnesol by any method known to the person skilled in the art.
  • the present invention is also directed to a process for the manufacture of isophytol and for the
  • a further object of the present invention is a process for the manufacture of isophytol comprising the following steps: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
  • the isophytol may be produced according to a process comprising the following steps which is also an object of the present invention: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
  • a further object of the present invention is a process for the manufacture of a-tocopherol and a-tocopheryl acetate, respectively, comprising the following steps: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention; b) converting (2E,6E)-farnesal either by a Wittig reaction or by an aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth- Emmons chemistry using a suitable phosphonate to obtain a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone according to the process of the present invention;
  • the a-tocopherol or its acetate may be produced according to a process comprising the following steps which is also an object of the present invention: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
  • the steps d1 ), e1 ), d2) and f) may be carried out according to methods known to the person skilled in the art.
  • the ethynylation e.g. may either be performed with acetylene, ammonia and potassium hydroxide or with ethynyl Grignard.
  • the present invention is directed to a process for the manufacture of 6,10, 14-trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon- oxygen double bonds.
  • This process is an important step in the process for the manufacture of isophytol and ⁇ -tocopherol or its acetate.
  • a mixture where the amount of non- (3EZ,5E,9E)-3,4-dehydrofarnesylacetone isomers is up to 49 mol-%, preferably up to 20 mol-%, more preferably up to 10 mol-%, based on the total amount of the mixture, may also be used successfully. More
  • (3E,5E,9Z)-3,4-dehydrofarnesylacetone, (3E, 5Z,9Z)-3,4-dehydrofarnesyl- acetone, (3Z, 5E,9Z)-3,4-dehydrofarnesylacetone and (3Z, 5Z,9Z)-3,4- dehydrofarnesylacetone are only present in traces, i.e. in an amount of less than 0.5 mol-% each, more preferably in an amount of less than 0.1 mol-% each. Most preferably a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone is used, where neither
  • the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof. Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.
  • a support/carrier being selected from the group consisting of carbon, graphite, inorganic oxides, inorganic carbonates, inorganic sulfates, as well as mixtures thereof where the active component (i.e. the metal) is deposited on.
  • Preferred support/carrier materials are carbon, silicon dioxide, aluminum oxide and calcium carbonate, as well as mixtures thereof.
  • An example for such mixtures are silica-alumina-mixtures.
  • the most preferred catalysts according to the present invention are palladium on carbon and palladium on alumina. If the active metal is used on a support/carrier material, the active metal content is preferably in the range of from 0.5 to 20 weight%, more preferably in the range of from 2 to 5 weight%, most preferably in the range of approximately 5 weight%, based on the total weight of active metal and support.
  • the amount of the active component of the catalyst (being preferably a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof) is preferably in the range of from 0.0001 to 1 weight%, more preferably in the range of from 0.001 to 0.5 weight%, most preferably in the range of from 0.01 to 0.1 weight%, based on the weight of the starting material, the mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone.
  • the hydrogenation reaction is preferably carried out at a temperature in the range of from 10 to 150° C, more preferably at a temperature in the range of from 20 to 100° C, most preferably at a temperature in the range of from 50 to 90 ° C.
  • the hydrogenation reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar hydrogen absolute, more preferably at a hydrogen pressure in the range of from 2 to 10 bar hydrogen absolute, even more preferably at a hydrogen pressure in the range of from 2 to 6 bar hydrogen absolute, further more preferably at a hydrogen pressure in the range of from 2.5 to 4 bar hydrogen absolute most preferably at a hydrogen pressure of around 3 bar hydrogen absolute.
  • the hydrogenation reaction can be carried without solvent or in the presence of an organic solvent.
  • the reaction is carried out in an organic solvent.
  • the organic solvent is preferably selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles and ketones and mixtures thereof. More preferred are C 4 -Cio
  • Ci -C 4 linear alkyl groups or C 3 -C 4 branched alkyl groups or halogens Ci -C 4 linear alcohols or C 3 -C 4 branched alcohols
  • acyclic and cyclic C 4 -Cio ethers Ci -Cio esters, C 3 -Cio ketones and mixtures thereof.
  • Especially preferred organic solvents are selected from the group consisting of hexane, heptane, toluene, methanol, ethanol, n-propanol, 2-propanol, n- butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof.
  • the most preferred solvent is heptane.
  • a mixture of the substrate dehydrofarnesylacetone (200 mg) (either a mixture of (3EZ,5EZ,9E) or (3EZ,5EZ,9EZ) isomers and solvent (2 g) is added to a glass reactor.
  • the catalyst is added and the reactor is sealed.
  • the mixture is purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release).
  • the reactor is heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring is started at 1000 rpm and the hydrogen uptake is recorded. After a total experiment time of 18 hours the reaction mixture is cooled to room temperature, the pressure is released and a sample taken for GC area% analysis.
  • the following catalysts are used: - a 5% Pd/Al 2 0 3 egg-shell catalyst with a BET surface area of 93 m 2 /g and a pore volume of 0.3 ml/g as e.g. commercially available from Evonik under the tradename "5% Pd/Al 2 0 3 E 213 R/D";

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention is directed to a process for the manufacture of 6,10,14-trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds. Preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. A process for the preparation of (2E,6E)-farnesal by selective oxidation of (2E,6E)-farnesol and a process for the manufacture of a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone from (2E,6E)-farnesal is also disclosed.

Description

PROCESS FOR THE MANUFACTURE OF 6,1 0,14-TRIMETHYLPENTADECAN-2-ONE, ISOPHYTOL AND ALPHA-TOCOPHEROL
The present invention is directed to a process for the manufacture of 6, 10, 1 -trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon-oxygen double bonds (see Fig. 3). Preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof. Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.
Surprisingly the inventors of the present invention discovered that when a mixture of (3E, 5E,9E)-3,4-dehydrofarnesylacetone and (31,
5E,9E)-3,4-dehydrofarnesylacetone is used to obtain C18-ketone, the hydrogenation reaction is much faster than in the case, where a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone, (3Z,5E,9E)-3,4- dehydrofarnesylacetone, (3E, 5Z,9E)-3,4-dehydrofarnesylacetone,
(3Z,5Z,9E)-3,4-dehydrofarnesylacetone, (3E,5E,9Z)-3,4- dehydrofarnesylacetone, (3E,5Z,9Z)-3,4-dehydrofarnesylacetone,
(3Z,5E,9Z)-3,4-dehydrofarnesylacetone and (3Z, 5Z,9Z)-3,4-dehydro- farnesylacetone or any other mixture of the double bond stereoisomers of 3,4-dehydrofarnesylacetone comprising more double bond stereoisomers than the two isomers (3E, 5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)- 3,4-dehydrofarnesylacetone is used. Therefore, it is advantageous, especially for an industrial process, where hundreds of tons are produced, to use as starting material for obtaining C18-ketone a mixture of (3E,5E,9E)- 3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone, because the time savings have an immense influence on the overall production costs.
Manufacture of a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone
Such a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)- 3,4-dehydrofarnesylacetone can be obtained from (2E,6E)-farnesal (see Fig.
2), either by a Wittig reaction with e.g. 2-oxopropyltriphenylphosphonium chloride (or the equivalent bromide or iodide salt) (I) or by an aldol condensation with acetone (II) and a base (whereby dehydrofarnesylacetone is predominantly obtained as the (3EZ,5E,9E) isomer) or by a Knoevenagel reaction (III) followed by decarboxylation or by Horner-Wadsworth-Emmons chemistry using a suitable phosphonate, for example dimethyl 2-oxopropyl- phosphonate or diethyl 2-oxopropylphosphonate. This synthesis of (2E,6E)- farnesal is also an embodiment of the present invention.
Figure imgf000003_0001
Manufacture of (2E,6E)-farnesal (see Fig. 1 )
(2E,6E)-Farnesal can be obtained by selective oxidation of (2E,6E)-farnesol (see Fig. 1 ), e.g. by the use of manganese oxide in a solvent with only a small change in the carbon-carbon double bond geometry. Alternatively, oxygen and palladium catalysts as described in Kakiuchi et al, Bull Chem Soc Jpn, 2001 , 165-172 (especially page 168, Table 3, example 11 ) may be used for the selective oxidation of (2E,6E)-farnesol to (2E,6E)-farnesal. This selective oxidation is also an embodiment of the present invention. The (2E,6E)-farnesol may itself be extracted from natural sources or obtained by fermentation or synthesized synthetically and, if needed, separated from (2Z,6E)-, (2E,6Z)- and (2Z,6Z)-farnesol by any method known to the person skilled in the art.
Process for the manufacture of isophytol, g-tocopherol and g-tocophery acetate
Since the mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)- 3,4-dehydrofarnesylacetone is an important starting material for isophytol, and thus for a-tocopherol and its acetate, the present invention is also directed to a process for the manufacture of isophytol and for the
manufacture of α-tocopherol and its acetate, respectively, comprising the process according to the present invention. Therefore, a further object of the present invention is a process for the manufacture of isophytol comprising the following steps: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
b) converting (2E,6E)-farnesal either by a Wittig reaction or by an
aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth- Emmons chemistry using a suitable phosphonate to obtain a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone according to the process of the present invention;
c) hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst according to the process of the present invention to obtain 6, 10,14-trimethylpentadecan-2-one; d1 ) ethynylating 6, 10, 1 -trimethylpentadecan-2-one to obtain
3,7, 1 1 , 15-tetramethylhexadec-1 -yn-3-ol;
e1 ) hydrogenating 3,7, 1 1 , 1 5-tetramethylhexadec-1 -yn-3-ol to isophytol. Alternatively, the isophytol may be produced according to a process comprising the following steps which is also an object of the present invention: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
b) converting (2E,6E)-farnesal either by a Wittig reaction or by an
aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth- Emmons chemistry using a suitable phosphonate to obtain a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone according to the process of the present invention;
c) hydrogenating a mixture of (3E, 5E,9E)-3,4-dehydrofarnesylacetone and (3Z, 5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst according to the process of the present invention to obtain 6, 10, 14-trimethylpentadecan-2-one;
d2) vinylating 6, 10, 14-trimethylpentadecan-2-one by addition of a vinyl Grignard reagent to yield isophytol.
A further object of the present invention is a process for the manufacture of a-tocopherol and a-tocopheryl acetate, respectively, comprising the following steps: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention; b) converting (2E,6E)-farnesal either by a Wittig reaction or by an aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth- Emmons chemistry using a suitable phosphonate to obtain a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone according to the process of the present invention;
c) hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst according to the process of the present invention to obtain 6,10, 14-trimethylpentadecan-2-one;
d1 ) ethynylating 6,10, 14-trimethylpentadecan-2-one to obtain
3,7, 11 ,15- tetramethylhexadec-1 -yn-3-ol;
e1 ) hydrogenating 3,7, 11 , 15-tetramethylhexadec-1 -yn-3-ol to isophytol;
f) coupling isophytol with 2,3,5-trimethylhydroquinone or its
acetate to obtain a-tocopherol or its acetate.
Alternatively, the a-tocopherol or its acetate (a-tocopheryl acetate) may be produced according to a process comprising the following steps which is also an object of the present invention: a) selectively oxidizing (2E,6E)-farnesol to (2E,6E)-farnesal according to the process of the present invention;
b) converting (2E,6E)-farnesal either by a Wittig reaction or by an aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth- Emmons chemistry using a suitable phosphonate to obtain a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone according to the process of the present invention; c) hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst according to the process of the present invention to obtain 6,10, 1 -trimethylpentadecan-2-one;
d2) vinylating 6,10, 14-trimethylpentadecan-2-one by addition of a vinyl Grignard reagent to yield isophytol;
f) condensing isophytol with 2,3,5-trimethylhydroquinone or its acetate to obtain a-tocopherol or its acetate.
The steps d1 ), e1 ), d2) and f) may be carried out according to methods known to the person skilled in the art. The ethynylation e.g. may either be performed with acetylene, ammonia and potassium hydroxide or with ethynyl Grignard. The following hydrogenation of the CC triple bond to a C=C double bond is then carried out with a Lindlar catalyst.
Detailed description
There was a need to further optimize the synthesis of isophytol, an important starting material for a-tocopherol and its acetate (a-tocopheryl acetate). 6,10, 14-trimethylpentadecan-2-one (in the following called "C18- ketone") is the starting material for isophytol. Thus, an improvement in the synthesis of C18-ketone leads also to an improvement in the synthesis of isophytol.
This need is fulfilled by the present invention, which is directed to a process for the manufacture of 6,10, 14-trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon-carbon double bonds over carbon- oxygen double bonds. This process is an important step in the process for the manufacture of isophytol and α-tocopherol or its acetate. Starting material
Preferably a mixture of (3E, 5E,9E)-3,4-dehydrofarnesylacetone and
(3Z,5E,9E)-3,4-dehydrofarnesylacetone is used, where the content of other C=C double bond stereoisomers is below 50 mol-%, preferably below 20 mol- %, more preferably below 10 mol-%, even more preferably below 5 mol-%, most preferably below 2 mol-% or below 0.5 mol-%, based on the total amount of the mixture. Thus, a mixture, where the amount of non- (3EZ,5E,9E)-3,4-dehydrofarnesylacetone isomers is up to 49 mol-%, preferably up to 20 mol-%, more preferably up to 10 mol-%, based on the total amount of the mixture, may also be used successfully. More
preferably, however, a mixture of (3E, 5E,9E)-3,4-dehydrofarnesylacetone and (3Z, 5E,9E)-3,4-dehydrofarnesylacetone is used, where (3E, 5Z,9E)-3,4- dehydrofarnesylacetone, (3Z,5Z,9E)-3,4-dehydrofarnesylacetone,
(3E,5E,9Z)-3,4-dehydrofarnesylacetone, (3E, 5Z,9Z)-3,4-dehydrofarnesyl- acetone, (3Z, 5E,9Z)-3,4-dehydrofarnesylacetone and (3Z, 5Z,9Z)-3,4- dehydrofarnesylacetone are only present in traces, i.e. in an amount of less than 0.5 mol-% each, more preferably in an amount of less than 0.1 mol-% each. Most preferably a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone is used, where neither
(3E,5Z,9E)-3,4-dehydrofarnesylacetone nor (3Z,5Z,9E)-3,4- dehydrofarnesylacetone nor (3E,5E,9Z)-3,4-dehydrofarnesylacetone nor (3E,5Z,9Z)-3,4-dehydrofarnesylacetone nor (3Z, 5E,9Z)-3,4- dehydrofarnesylacetone nor (3Z, 5Z,9Z)-3,4-dehydrofarnesylacetone are present.
Catalyst
Preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof. More preferably the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof. Even more preferably the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof. Most preferably the catalyst is palladium.
Of the catalysts described above, those catalysts are even more preferred that comprise a support/carrier being selected from the group consisting of carbon, graphite, inorganic oxides, inorganic carbonates, inorganic sulfates, as well as mixtures thereof where the active component (i.e. the metal) is deposited on. Preferred support/carrier materials are carbon, silicon dioxide, aluminum oxide and calcium carbonate, as well as mixtures thereof. An example for such mixtures are silica-alumina-mixtures.
The most preferred catalysts according to the present invention are palladium on carbon and palladium on alumina. If the active metal is used on a support/carrier material, the active metal content is preferably in the range of from 0.5 to 20 weight%, more preferably in the range of from 2 to 5 weight%, most preferably in the range of approximately 5 weight%, based on the total weight of active metal and support.
The amount of the active component of the catalyst (being preferably a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof) is preferably in the range of from 0.0001 to 1 weight%, more preferably in the range of from 0.001 to 0.5 weight%, most preferably in the range of from 0.01 to 0.1 weight%, based on the weight of the starting material, the mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone.
Reaction conditions The hydrogenation reaction is preferably carried out at a temperature in the range of from 10 to 150° C, more preferably at a temperature in the range of from 20 to 100° C, most preferably at a temperature in the range of from 50 to 90° C. The hydrogenation reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar hydrogen absolute, more preferably at a hydrogen pressure in the range of from 2 to 10 bar hydrogen absolute, even more preferably at a hydrogen pressure in the range of from 2 to 6 bar hydrogen absolute, further more preferably at a hydrogen pressure in the range of from 2.5 to 4 bar hydrogen absolute most preferably at a hydrogen pressure of around 3 bar hydrogen absolute.
Solvent
The hydrogenation reaction can be carried without solvent or in the presence of an organic solvent. Preferably the reaction is carried out in an organic solvent.
The organic solvent is preferably selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles and ketones and mixtures thereof. More preferred are C4-Cio
aliphatic hydrocarbons, C6-Cio aromatic hydrocarbons, C6-Cio aromatic hydrocarbons substituted with one or more Ci -C4 linear alkyl groups or C3-C4 branched alkyl groups or halogens, Ci -C4 linear alcohols or C3-C4 branched alcohols, acyclic and cyclic C4-Cio ethers, C3-Cio esters, C3-Cio ketones and mixtures thereof.
Especially preferred organic solvents are selected from the group consisting of hexane, heptane, toluene, methanol, ethanol, n-propanol, 2-propanol, n- butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof. The most preferred solvent is heptane. The amount of solvent is preferably in the range of from 0 to 100 volumes (0 = solvent free), more preferably in the range of from 0.1 to 10 volumes, most preferably in the range of from 1 to 5 volumes, based on the volume of the starting material, the mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone.
The invention is now further illustrated in the following non-limiting examples. Examples
Standard Protocol for Hydrogenation Reactions
A mixture of the substrate dehydrofarnesylacetone (200 mg) (either a mixture of (3EZ,5EZ,9E) or (3EZ,5EZ,9EZ) isomers and solvent (2 g) is added to a glass reactor. The catalyst is added and the reactor is sealed. The mixture is purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release). The reactor is heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring is started at 1000 rpm and the hydrogen uptake is recorded. After a total experiment time of 18 hours the reaction mixture is cooled to room temperature, the pressure is released and a sample taken for GC area% analysis.
Hydrogenation Results
The examples given below show that the hydrogenation of (3EZ,5EZ,9E) - dehydrofarnesylacetone proceeds faster than the hydrogenation of
(3EZ,5EZ,9EZ)-dehydrofarnesylacetone.
The following catalysts are used: - a 5% Pd/Al203 egg-shell catalyst with a BET surface area of 93 m2/g and a pore volume of 0.3 ml/g as e.g. commercially available from Evonik under the tradename "5% Pd/Al203 E 213 R/D";
- a 5% Pd/C as e.g. commercially available from Evonik under the tradename "5% Pd/C E 101 O/D"
Table 1 : Catalyst used = 5% Palladium on Carbon as commercially available from Evonik
Figure imgf000013_0001

Claims

Claims
A process for the manufacture of 6, 10, 14-trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (3E,5E,9E)-3,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4- dehydrofarnesylacetone with hydrogen in the presence of a catalyst, whereby the catalyst is capable of preferentially hydrogenating carbon- carbon double bonds over carbon-oxygen double bonds.
The process according to claim 1 , whereby the catalyst preferably comprises a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof, more preferably whereby the catalyst comprises a metal selected from the group consisting of palladium, platinum and mixtures thereof, even more preferably whereby the catalyst is a metal selected from the group consisting of palladium, platinum and mixtures thereof, most preferably whereby the catalyst is palladium.
The process according to claim 1 and/or 2, whereby the catalyst preferably comprises a carrier/support being selected from the group consisting of carbon, graphite, inorganic oxides, inorganic carbonates, inorganic sulfates, as well as mixtures thereof where the metal is deposited on, more preferably the catalyst comprises a carrier/support being selected from the group consisting of carbon, silicon dioxide, aluminum oxide and calcium carbonate, as well as mixtures thereof, where the metal is deposited on.
The process according to one or more of claims 1 to 3, wherein the hydrogenation reaction is carried out at a temperature in the range of from 10 to 150° C, preferably at a temperature in the range of from 20 to 100° C, more preferably at a temperature in the range of from 50 to 90° C.
The process according to any one or more of claims 1 to 4, wherein the hydrogenation reaction is carried out at a hydrogen pressure in the range of from 1 to 25 bar hydrogen absolute, preferably at a hydrogen pressure in the range of from 2 to 10 bar hydrogen absolute, more preferably at a hydrogen pressure in the range of from 2 to 6 bar hydrogen absolute, even more preferably at a hydrogen pressure in the range of from 2.5 to 4 bar hydrogen absolute, most preferably at a hydrogen pressure of around 3 bar hydrogen absolute.
The process according to any one or more of claims 1 to 5, wherein the amount of the active component of the catalyst (being preferably a metal selected from the group consisting of palladium, platinum, rhodium, iridium and nickel and mixtures thereof) is in the range of from 0.0001 to 1 .0 weight-%, preferably in the range of from 0.001 to 0.5 weight-%, more preferably in the range of from 0.01 to 0.1 weight-%, based on the weight of the starting material, the mixture of (3E,5E,9E)-3,4-dehydro-farnesyl- acetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone.
The process according to any one or more of claims 1 to 6, wherein the hydrogenation reaction is carried out in an organic solvent.
The process according to claim 7, wherein the organic solvent is selected from the group consisting of hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles and ketones and mixtures thereof, preferably wherein the organic solvent is selected from the group consisting of C4-C10 aliphatic hydrocarbons, C6-Ci o aromatic hydrocarbons, C0-C10 aromatic hydrocarbons substituted with one or more C1 -C4 linear alkyl groups or C3-C4 branched alkyl groups or halogens, C1 -C4 linear alcohols or C3-C4 branched alcohols, acyclic and cyclic C4-C10 ethers, C3-C10 esters, C3-C10 ketones and mixtures thereof.
9. The process according to claim 8, wherein the organic solvent is selected from the group consisting of hexane, heptane, toluene, methanol, ethanol, n-propanol, 2-propanol, n-butanol, tetrahydrofuran, 2-methyl- tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof
10. The process according to any one or more of claims 7 to 9, wherein the amount of solvent is in the range of from 0.01 to 100 volumes, more preferably in the range of from 0.1 to 10 volumes, most preferably in the range of from 1 to 5 volumes, based on the volume of the starting material, the mixture of (3E,5E,9E)-3 ,4-dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone.
1 1 . The process according to any one or more of the preceding claims,
wherein the starting material, the mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone, is obtained from (2E,6E)-farnesal either by a Wittig reaction or by an aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth-Emmons chemistry using a suitable phosphonate.
12. The process according to claim 1 1 , wherein the (2E,6E)-farnesal is
obtained from (2E,6E)-farnesol by selective oxidation.
13. A process for the manufacture of isophytol comprising a process according to any one or more of the preceding claims.
A process for the manufacture of a-tocopherol or a-tocopheryl acetate comprising a process according to any one or more of the preceding claims.
A process for the manufacture of (2E,6E)-farnesal by selective oxidation of (2E,6E)-farnesol.
A process for the manufacture of a mixture of (3E,5E,9E)-3,4- dehydrofarnesylacetone and (3Z,5E,9E)-3,4-dehydrofarnesylacetone comprising the step of either reacting (2E,6E)-farnesal by a Wittig reaction or by an aldol condensation with acetone and a base or by a Knoevenagel reaction followed by decarboxylation or by Horner-Wadsworth-Emmons chemistry using a suitable phosphonate.
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