WO2017098049A1 - Process for the manufacture of 6,10,14-trimethylpentadecan-2-one - Google Patents

Process for the manufacture of 6,10,14-trimethylpentadecan-2-one Download PDF

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WO2017098049A1
WO2017098049A1 PCT/EP2016/080661 EP2016080661W WO2017098049A1 WO 2017098049 A1 WO2017098049 A1 WO 2017098049A1 EP 2016080661 W EP2016080661 W EP 2016080661W WO 2017098049 A1 WO2017098049 A1 WO 2017098049A1
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farnesylacetone
catalyst
range
process according
mixtures
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PCT/EP2016/080661
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French (fr)
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Werner Bonrath
Jonathan Alan Medlock
Thomas Mueller
Peter Hans RIEBEL
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Dsm Ip Assets B.V.
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Publication of WO2017098049A1 publication Critical patent/WO2017098049A1/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • 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

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
  • 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.
  • Such a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone can be obtained by C3 elongation of (E)-nerolidol.
  • An example is the reaction of (E)- nerolidol with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst to the mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone.
  • catalyst either an acid or an ammonium salt can be used.
  • the catalyst is an acid, preferably wherein the catalyst is selected from the group consisting of phosphoric acid, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, oxalic acid and mixtures thereof, is further described in WO 2009/019132 whose content is hereby incorporated by reference.
  • the catalyst is an ammonium salt, preferably wherein the catalyst is selected from the group consisting of ammonium bromide, ammonium chloride or di-ammonium phosphate, is further described in WO 2010/046199 whose content is hereby incorporated by reference.
  • C3 elongation of (E)-nerolidol may also be carried out with one of the following reagents according to processes known to the person skilled in the art.
  • An example of a process where diketene is used is described in GB 788,301 .
  • An example of a process where acetoacetic esters are used (so-called "Carroll reaction") is described in e.g. CN 102 115 437.
  • the (E)-nerolidol used as starting material may come from natural sources or any other source or obtained by fermentation or may be synthesized
  • a further access to (E)-nerolidol is starting from (E)-geranylacetone which may itself be extracted from natural sources or any other source or obtained by fermentation or synthesized synthetically and, if needed, separated from (Z)- geranyl acetone by any method known to the person skilled in the art.
  • the (E)-geranyl acetone is then ethynylated according to any process known to the person skilled in the art and afterwards hydrogenated in presence of a Lindlar catalyst.
  • the ethyinylation may either be performed with acetylene, ammonia and a base, for example potassium hydroxide or with an ethynyl Grignard.
  • (E)-geranyl acetone may be reacted with vinyl Grignard according to a process known by the person skilled in the art.
  • Still another approach to (E)-nerolidol is by rearrangement of (2E,6E)-farnesol, (2Z,6E)-farnesol or any mixture thereof as e.g. described by S. Matsubara, T. Okazoe, K. Oshima, K. Takai, H. Nozaki in Bull. Chem. Soc. Jpn. 1985, 58, 844- 849 and by J. Jacob, J. H. Espenson, J. H. Jensen, M. S. Gordon in
  • 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 (2Z,6E)-farnesol may itself be synthesized synthetically and, if needed, separated from (2E,6E)-, (2E,6Z)- and (2Z,6Z)-farnesol by any method known to the person skilled in the art.
  • the mixture of (2E,6E)-farnesol and (2Z,6E)-farnesol may itself be synthesized synthetically and, if needed, separated from (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 manufacture of a-tocopherol and its acetate, respectively, comprising the process according to the present invention.
  • a further object of the present invention is a process for the manufacture of isophytol comprising the following steps: a) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
  • the isophytol may be produced according to a process comprising the following steps which is also an object of the present invention: a) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
  • a further object of the present invention is a process for the manufacture of a- tocopherol and its acetate, respectively, comprising the following steps: a) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
  • 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) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one; c2) vinylating 6, 10, 14-trimethylpentadecan-2-one by addition of a vinyl Grignard reagent to yield isophytol;
  • the steps c1 ), d1 ), c2) and e) 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 (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone 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 corresponds to step b) in the process for the manufacture of isophytol and ⁇ -tocopherol or its acetate.
  • a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone is used, where the content of (5E,9Z) -farnesylacetone and (5Z,9Z)- farnesylacetone is below 43 mol-%, preferably below 20 mol-%, more preferably below 10 mol-%, based on the total amount of the mixture.
  • a mixture, where the amount of (5E,9Z) farnesylacetone and (5Z,9Z)-farnesylacetone is up to 43 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.
  • a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone is used, where (5E,9Z)-farnesylacetone and (5Z,9Z) -farnesylacetone are only present in traces, i.e. in an amount of below 0.5 mol-% each, preferably in an amount of below 0.1 mol-% each.
  • Most preferably a mixture of (5E,9E)- farnesylacetone and (5Z,9E)-farnesylacetone is used, where neither (5E,9Z)- farnesylacetone nor (5Z,9Z)-farnesylacetone are present.
  • 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.
  • 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. More preferred catalysts are palladium on carbon, palladium on silica and palladium on alumina; most preferred is palladium on alumina.
  • the active component (i.e. the metal) is used on a support/carrier material
  • the active component (i.e. the 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 the active component (i.e. the metal) and the support.
  • the amount of the active component of the catalyst 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 (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone.
  • 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 out 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.
  • C4-C10 aliphatic hydrocarbons More preferred are C4-C10 aliphatic hydrocarbons, C 6 -Cio aromatic hydrocarbons, C 6 -Ci o 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.
  • 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.
  • All isomers means a mixture of (5E,9E)-farnesylacetone, (5Z,9E)- farnesylacetone, (5E,9Z)-farnesylacetone and (5Z,9Z)-farnesylacetone.
  • a farnesylacetone (4 g) was added to a glass reactor.
  • the catalyst was added and the reactor was sealed.
  • the mixture was purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release).
  • the reactor was heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring was started at 1000 rpm and the hydrogen uptake was recorded. After a total experiment time of 18 hours the reaction mixture was cooled to room temperature, the pressure was released and a sample taken for GC analysis.
  • Catalyst used Evonik E 101 O/D (5% Palladium on carbon)

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  • 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 (5E, 9E)-farnesylacetone and (5Z, 9E)- farnesylacetone 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.

Description

Process for the manufacture of 6, 10, 14-trimethylpentadecan-2-one
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 (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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. 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.
Figure imgf000002_0001
9 5
farnesyl acetone
Surprisingly the inventors of the present invention discovered that when a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone is used to obtain C18-ketone, the hydrogenation reaction is much faster than in the case, where a mixture of (5E,9E)-farnesylacetone, (5Z,9E)-farnesylacetone, (5E,9Z) farnesylacetone and (5Z,9Z)-farnesylacetone 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 (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone, because the time savings have an immense influence on the overall production costs.
l Manufacture of a mixture of (5E,9E)-farnesylacetone and (5Z.9E)- farnesylacetone
Such a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone can be obtained by C3 elongation of (E)-nerolidol. An example is the reaction of (E)- nerolidol with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst to the mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone. As catalyst either an acid or an ammonium salt can be used. The process wherein the catalyst is an acid, preferably wherein the catalyst is selected from the group consisting of phosphoric acid, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, oxalic acid and mixtures thereof, is further described in WO 2009/019132 whose content is hereby incorporated by reference.
The process wherein the catalyst is an ammonium salt, preferably wherein the catalyst is selected from the group consisting of ammonium bromide, ammonium chloride or di-ammonium phosphate, is further described in WO 2010/046199 whose content is hereby incorporated by reference.
Alternatively the C3 elongation of (E)-nerolidol may also be carried out according to the process as described in JP-A 2002-121 165.
Furthermore the C3 elongation of (E)-nerolidol may also be carried out with one of the following reagents according to processes known to the person skilled in the art.
Figure imgf000003_0001
An example of a process where diketene is used is described in GB 788,301 . An example of a process where acetoacetic esters are used (so-called "Carroll reaction") is described in e.g. CN 102 115 437.
Manufacture of (E)-nerolidol
The (E)-nerolidol used as starting material may come from natural sources or any other source or obtained by fermentation or may be synthesized
synthetically and, if needed, separated from (Z)-nerolidol by any method known to the person skilled in the art.
A further access to (E)-nerolidol is starting from (E)-geranylacetone which may itself be extracted from natural sources or any other source or obtained by fermentation or synthesized synthetically and, if needed, separated from (Z)- geranyl acetone by any method known to the person skilled in the art.
Figure imgf000004_0001
E E
(E)-Geranylacetone (E)-Nerolidol
The (E)-geranyl acetone is then ethynylated according to any process known to the person skilled in the art and afterwards hydrogenated in presence of a Lindlar catalyst. The ethyinylation may either be performed with acetylene, ammonia and a base, for example potassium hydroxide or with an ethynyl Grignard. Alternatively (E)-geranyl acetone may be reacted with vinyl Grignard according to a process known by the person skilled in the art.
Still another approach to (E)-nerolidol is by rearrangement of (2E,6E)-farnesol, (2Z,6E)-farnesol or any mixture thereof as e.g. described by S. Matsubara, T. Okazoe, K. Oshima, K. Takai, H. Nozaki in Bull. Chem. Soc. Jpn. 1985, 58, 844- 849 and by J. Jacob, J. H. Espenson, J. H. Jensen, M. S. Gordon in
Organometallics 1998, 17, 1835-1840.
Figure imgf000005_0001
E E/Z
(2E/2Z,6E)-Farnesol (E)-Nerolidol
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 (2Z,6E)-farnesol may itself be synthesized synthetically and, if needed, separated from (2E,6E)-, (2E,6Z)- and (2Z,6Z)-farnesol by any method known to the person skilled in the art.
The mixture of (2E,6E)-farnesol and (2Z,6E)-farnesol may itself be synthesized synthetically and, if needed, separated from (2E,6Z)- and (2Z,6Z)-farnesol by any method known to the person skilled in the art.
Process for the manufacture of isophytol, g-tocophero and its acetate
Since the mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone 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 a-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) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
c1 ) ethynylating 6, 10, 14-trimethylpentadecan-2-one to obtain 3,7, 1 1 , 15- tetramethylhexadec-1 -yn-3-ol;
d1 ) hydrogenating 3,7, 1 1 , 15-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) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
c2) 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 its acetate, respectively, comprising the following steps: a) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one;
c1 ) ethynylating 6, 10, 1 -trimethylpentadecan-2-one to obtain 3,7, 11 , 15- tetramethylhexadec-1 -yn-3-ol;
d1 ) hydrogenating 3,7, 11 ,15-tetramethylhexadec-1 -yn-3-ol to isophytol; e) coupling isophytol with 2,3,5-trimethylhydroquinone or its acetate to obtain a-tocopherol or its acetate.
Alternatively, 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) C3 prolonging (E)-nerolidol, preferably with isopropenyl methyl ether or with isopropenyl ethyl ether, in the presence of a catalyst to obtain a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone; b) hydrogenating a mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone 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, to obtain 6, 10, 14- trimethylpentadecan-2-one; c2) vinylating 6, 10, 14-trimethylpentadecan-2-one by addition of a vinyl Grignard reagent to yield isophytol;
e) condensing isophytol with 2,3,5-trimethylhydroquinone or its acetate to obtain a-tocopherol or its acetate.
The steps c1 ), d1 ), c2) and e) 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. 6,10,14-trimethylpenta- decan-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 (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone 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 corresponds to step b) in the process for the manufacture of isophytol and α-tocopherol or its acetate.
Starting material
Preferably a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone is used, where the content of (5E,9Z) -farnesylacetone and (5Z,9Z)- farnesylacetone is below 43 mol-%, preferably below 20 mol-%, more preferably below 10 mol-%, based on the total amount of the mixture. Thus, a mixture, where the amount of (5E,9Z) farnesylacetone and (5Z,9Z)-farnesylacetone is up to 43 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 a mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone is used, where (5E,9Z)-farnesylacetone and (5Z,9Z) -farnesylacetone are only present in traces, i.e. in an amount of below 0.5 mol-% each, preferably in an amount of below 0.1 mol-% each. Most preferably a mixture of (5E,9E)- farnesylacetone and (5Z,9E)-farnesylacetone is used, where neither (5E,9Z)- farnesylacetone nor (5Z,9Z)-farnesylacetone 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. More preferred catalysts are palladium on carbon, palladium on silica and palladium on alumina; most preferred is palladium on alumina.
If the active component (i.e. the metal) is used on a support/carrier material, the active component (i.e. the 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 the active component (i.e. the metal) and the 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 (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone.
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 out 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-C10 aliphatic hydrocarbons, C6-Cio aromatic hydrocarbons, C6-Ci o 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.
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 (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone.
The invention is now further illustrated in the following non-limiting examples. Examples
Standard Protocol for Hydrogenation Reactions
A mixture of the substrate farnesylacetone (20 g) and heptane (20 g) were added to a 125 ml steel autoclave. The catalyst was added and the reactor was sealed. The mixture was purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release). The reactor was heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring was started at 1000 rpm and the hydrogen uptake was recorded. After a total experiment time of 18 hours the reaction mixture was cooled to room temperature, the pressure was released and a sample taken for quantitative GC analysis. Hydrogenation Results
"All isomers" means a mixture of (5E,9E)-farnesylacetone, (5Z,9E)- farnesylacetone, (5E,9Z)-farnesylacetone and (5Z,9Z)-farnesylacetone.
The following catalysts were 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/CaC03 egg-shell catalyst with a BET surface area of 8 m2/g, a bulk density of 0.37 kg/l, and whereby 50% of the particles have a size < 5 μητι as e.g. commercially available from Evonik under the tradename "5% Pd/CaC03 E 407 R/D".
- a 5% Palladium on carbon catalyst e.g. commercially available from Evonik under the tradename "5% Pd/C E 101 O/D";
- a 5% Palladium on Silica catalyst as commercially available from Johnson Matthey. The results are summarized in tables 1 -4.
Standard Protocol for Solvent-free Hydrogenation Reactions
A farnesylacetone (4 g) was added to a glass reactor. The catalyst was added and the reactor was sealed. The mixture was purged three times with nitrogen (pressurise to 5 bar, then release) and three times with hydrogen (pressurise to 5 bar, then release). The reactor was heated to the desired temperature and then pressurised with hydrogen to the desired pressure. Stirring was started at 1000 rpm and the hydrogen uptake was recorded. After a total experiment time of 18 hours the reaction mixture was cooled to room temperature, the pressure was released and a sample taken for GC analysis.
The results are summarized in tables 5-6.
Table 1 : Catalyst used = Evonik E 101 O/D (5% Palladium on carbon)
Figure imgf000014_0001
Table 3: Catalyst used = 5% Palladium on Silica as commercially available from Johnson Matthey
Figure imgf000015_0001
Table 4: Catalyst used = Evonik E 407 R/D (5% Palladium on Calcium Carbonate)
Figure imgf000015_0002
In both examples 9 and 10 no complete hydrogenation was achieved with 900 minutes. Therefore, samples were taken after this period of time and analysed.
Table 5: Catalyst used = Evonik E 101 O/D (5% Palladium on carbon)
Figure imgf000016_0001
For examples 11 and 13, the reactions were not complete after 1300 minutes and so were stopped and analysed. The starting material was fully converted but a mixture of the desired C18-ketone and intermediate products was found.
Table 6: Catalyst used = Evonik E 213 R/D (5% Palladium on Alumina)
Figure imgf000017_0001
For Example 18, 4.0 g of (5E,9E)/(5Z,9E) farnesylacetone (90% purity) gave, after filtration of the catalyst, 86% yield of C18-ketone.

Claims

Claims
A process for the manufacture of 6, 10, 14-trimethylpentadecan-2-one ("C18-ketone") comprising the step of hydrogenating a mixture of (5E,9E)- farnesylacetone and (5Z,9E)-farnesylacetone 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 metal is preferably deposited on a carrier/support being selected from the group consisting of carbon, graphite, inorganic oxides, inorganic carbonates, inorganic sulfates, as well as mixtures thereof, more preferably the metal is deposited on a carrier/support being selected from the group consisting of carbon, silicon dioxide, aluminum oxide and calcium carbonate, as well as mixtures thereof.
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.
5. 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.
6. 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 (5E,9E)-farnesylacetone and
(5Z , 9E ) -f arnesylacetone .
7. The process according to any one or more of claims 1 to 6, wherein the hydrogenation reaction is carried out in an organic solvent, preferably 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-Cio aromatic hydrocarbons, C6-Ci o 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, more preferably 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.
8. The process according to claim 7, 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 (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone.
9. The process according to any one or more of the preceding claims,
wherein the starting material, the mixture of (5E,9E)-farnesylacetone and (5Z,9E)-farnesylacetone, is obtained by reacting (E)-nerolidol with isopropenyl methyl ether or with isopropenyl ethyl ether in the presence of a catalyst.
10. The process according to claim 9, wherein the catalyst is an acid,
preferably wherein the catalyst is selected from the group consisting of phosphoric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, oxalic acid and mixtures thereof.
Figure imgf000020_0001
The process according to claim 9, wherein the catalyst is an ammonium salt, preferably wherein the catalyst is selected from the group consisting of ammonium bromide, ammonium chloride or di-ammonium phosphate. 12. The process according to any one or more of the preceding claims,
wherein the mixture of (5E,9E)-farnesylacetone and (5Z,9E)- farnesylacetone contains (5E,9Z)-farnesylacetone and (5Z,9Z)- farnesylacetone, and wherein the content of (5E,9Z)-farnesylacetone and (5Z,9Z)-farnesylacetone is below 43 mol-%, preferably below 20 mol-%, more preferably below 10 mol-%, based on the total amount of the mixture.
The process according to claim 1 1 , wherein the mixture of (5E,9E)- farnesylacetone and (5Z,9E)-farnesylacetone contains neither (5E,9Z)- farnesylacetone nor (5Z,9Z)-farnesylacetone.
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 its acetate comprising a process according to any one or more of the preceding claims.
PCT/EP2016/080661 2015-12-11 2016-12-12 Process for the manufacture of 6,10,14-trimethylpentadecan-2-one WO2017098049A1 (en)

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