U.S. patent application number 16/063481 was filed with the patent office on 2018-12-27 for intermolecular reaction of propargyl ethers with dimethylfuran in the presence of gold(i) complexes.
This patent application is currently assigned to DSM IP Assets B.V.. The applicant listed for this patent is DSM IP Assets B.V.. Invention is credited to Stephan ACKERMANN, Hajo LEHMANN, Ulla LETINOIS, Jonathan Alan MEDLOCK.
Application Number | 20180370887 16/063481 |
Document ID | / |
Family ID | 55168094 |
Filed Date | 2018-12-27 |
United States Patent
Application |
20180370887 |
Kind Code |
A1 |
LETINOIS; Ulla ; et
al. |
December 27, 2018 |
INTERMOLECULAR REACTION OF PROPARGYL ETHERS WITH DIMETHYLFURAN IN
THE PRESENCE OF GOLD(I) COMPLEXES
Abstract
The present invention relates to a method of preparing ortho
substituted phenols from 2,5-dimethylfuran and propargyl ethers in
the presence of a gold(I) complex. It is particularly advantageous
to use 2,5-dimethylfuran as this offers an ecological beneficial
synthesis of said ortho substituted phenols.
Inventors: |
LETINOIS; Ulla;
(Kaiseraugst, CH) ; ACKERMANN; Stephan;
(Kaiseraugst, CH) ; MEDLOCK; Jonathan Alan;
(Kaiseraugst, CH) ; LEHMANN; Hajo; (Kaiseraugst,
CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DSM IP Assets B.V. |
Heerlen |
|
NL |
|
|
Assignee: |
DSM IP Assets B.V.
Heerlen
NL
|
Family ID: |
55168094 |
Appl. No.: |
16/063481 |
Filed: |
November 28, 2016 |
PCT Filed: |
November 28, 2016 |
PCT NO: |
PCT/EP2016/079016 |
371 Date: |
June 18, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 43/1783 20130101;
B01J 31/2404 20130101; C07C 37/50 20130101; C07C 46/08 20130101;
C07C 37/07 20130101; B01J 31/2273 20130101; C07C 41/36 20130101;
C07C 41/30 20130101; C07D 311/72 20130101; B01J 31/183 20130101;
B01J 2531/18 20130101; C07C 41/30 20130101; C07C 43/1783 20130101;
C07C 41/36 20130101; C07C 43/1783 20130101; C07C 46/08 20130101;
C07C 50/02 20130101; C07C 37/07 20130101; C07C 39/08 20130101; C07C
37/50 20130101; C07C 39/07 20130101 |
International
Class: |
C07C 41/30 20060101
C07C041/30; C07C 43/178 20060101 C07C043/178; C07C 37/07 20060101
C07C037/07; C07C 37/50 20060101 C07C037/50; C07C 39/07 20060101
C07C039/07; C07C 39/08 20060101 C07C039/08; B01J 31/24 20060101
B01J031/24; B01J 31/22 20060101 B01J031/22; B01J 31/18 20060101
B01J031/18 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2015 |
EP |
EP15201770.3 |
Claims
1. A process of preparing a compound of formula (I) ##STR00026##
comprising the step of reacting compound of formula (II) with
compound of formula (III) ##STR00027## wherein R.sup.1 represents a
C.sub.1-10-alkyl group or a C.sub.4-7-cycloalkyl group; in the
presence of a gold(I) complex.
2. The process according to claim 1, wherein R.sup.1 represents a
C.sub.1-6-alkyl group, preferably a C.sub.1-3-alkyl group, more
preferably a methyl group.
3. The process according to claim 1, wherein that the gold(I)
complex has the formula [Au(I)OL]AN wherein OL represents an
organic ligand and AN represents a single charged anion.
4. The process according to claim 1, wherein the gold(I) complex
has a single charged anion (AN) which is selected from the group
consisting of [BX.sub.4].sup.-, [PX.sub.6].sup.-,
[SbF.sub.6].sup.-, [ClO.sub.4].sup.-, CF.sub.3COO.sup.-,
sulfonates, particularly a sulfonate of formula (AN-II),
tetra(3,5-bis(trifluoromethyl)phenyl)borate (BAr.sub.F.sup.-),
tetraphenylborate, and anions of formula (AN-I); ##STR00028##
wherein X represents a halogen atom; and Y.sup.1 represents a
phenyl or a C.sub.1-8-alkyl group, which preferably is substituted
by at least one halogen atom.
5. The process according to claim 1, wherein the gold(I) complex
has an organic ligand (OL) which is either at least one phosphorous
containing ligand, particularly a phosphorous containing ligand
which is selected from the group consisting of formula (P1), (P2),
(P3), (P4), (P5), (P6), (P7) and (P8); or at least an
imidazole-2-ylidene ligand, particularly
1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene
(=compound of formula (IM)); or at least a 1H-1,2,3-triazol ligand,
particularly of formula (TR-1) or (TR-2) or (TR-3), more
particularly of formula (TR-3); ##STR00029## ##STR00030## wherein
R.sup.10 and R.sup.11 represent independently from each other
either H or a linear or branched C.sub.1-10-alkyl or
C.sub.4-10-cycloalkyl group; and wherein R.sup.12, R.sup.13,
R.sup.14 and R.sup.15 represent independently from each other H or
a linear or branched C.sub.1-6-alkyl group; n stands for an integer
of 1-6 and n' stands for 0 or 1 or 2.
6. The process according to claim 1, wherein the gold(I) complex is
prepared from a gold(I) chloro complex and a silver(I) salt.
7. The process according to claim 6 wherein 1 the gold (I) complex
is of formula [Au(I)OL]AN wherein OL represents an organic ligand
and AN represents a single charged anion and the gold (I) complex
is prepared by the reaction of Au(I)OLCl and AgAN.
8. The process according to claim 1, wherein the gold (I) complex
is of formula [Au(I)OL]AN wherein OL represents an organic ligand
and AN represents a single charged anion and the gold (I) complex
is prepared by the reaction of Au(I)OLCl and NaAN.
9. The process according to claim 1, wherein it comprises a
subsequent step a): a) separating the compound of formula (I) from
compound of formula (IVa) and/or formula (IVb) ##STR00031## wherein
the wavy line represents a carbon-carbon bond which is linked to
the adjacent carbon-carbon double bond so as to have said
carbon-carbon double bond either in the Z or in the
E-configuration.
10. The process according to claim 9, wherein compound of formula
(I) from compound of formula (IVa) and/or (IVb) are separated by
chromatography, particularly by chromatography using silica gel as
stationary phase.
11. Compound of formula (I) ##STR00032## wherein R.sup.1 represents
a C.sub.1-10-alkyl group or a C.sub.4-7-cycloalkyl group.
12. Composition comprising the compound of formula (I) and at least
the compound of formula (IVa) or (IVb) ##STR00033## wherein R.sup.1
represents a C.sub.1-10-alkyl group or a C.sub.4-7-cycloalkyl group
and the wavy line represents a carbon-carbon bond which is linked
to the adjacent carbon-carbon double bond so as to have said
carbon-carbon double bond either in the Z or in the
E-configuration.
13. Composition according to claim 12, wherein the total amount of
compound of formula (IVa) and (IVb) is at most 80% by weight,
preferably at most 70% by weight, more preferably at most 50% by
weight, even more preferably at most 20% by weight, most preferably
at most 10% by weight, relative to the weight of compound of
formula (I).
14. A process of reducing a compound of formula (I) ##STR00034## by
a reducing agent in the presence of a heterogeneous metal catalyst
to yield a compound of formula (A) ##STR00035## wherein the metal
is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and
Ru; wherein R.sup.1 represents a C.sub.1-10-alkyl group or a
C.sub.4-7-cycloalkyl group.
15. A process for the manufacture of the compound of formula (C)
from compound of formula (I) comprising the following steps a')
reducing the compound of formula (I) by the process according to
claim 14 to yield a compound of formula (A); ##STR00036## b')
oxidizing the compound of formula (A) to yield a compound of
formula (B) by an oxidizing agent ##STR00037## c') reducing the
compound of formula (B) to yield a compound of formula (C) by a
reducing agent ##STR00038##
16. A process for the manufacture of compound of formula (D) from
compound of formula (I) comprising the steps a') hydrogenate
compound of formula (I) by the process according to claim 14 to
yield compound of formula (A); ##STR00039## b') oxidizing the
compound of formula (A) to yield a compound of formula (B) by an
oxidizing agent ##STR00040## c') reducing the compound of formula
(B) to yield a compound of formula (C) by a reducing agent
##STR00041## d') condensing isophytol with the compound of formula
(C) to yield a compound of formula (D); ##STR00042##
17. A process according to claim 14, wherein the compound of
formula (I) is prepared by a method.
Description
TECHNICAL FIELD
[0001] The present invention relates to the field of
ortho-substituted phenols and their derivatives.
BACKGROUND OF THE INVENTION
[0002] Phenolic compounds are in general very interesting for a
variety of industrial products and can be used particularly as
intermediates for complex chemical syntheses.
[0003] Particular the class of ortho-substituted phenols, and even
more of ortho-disubstituted phenols, is very appealing due their
use as antioxidants.
[0004] Syntheses based on renewable raw materials are very
attractive from an ecological point of view as such syntheses, as
by this approach the dependency of chemical industry from the
diminishing fossil oil reserves can be strongly reduced. Y.
Roman-Leshkov et al., Nature 2007, 447, 982-985, discloses that
2,5-dimethylfuran can be obtained from biomass. Therefore,
2,5-dimethylfuran is a very interesting building block to be used
in chemical industries.
[0005] Furthermore, the use of staring materials from renewable
resources are advantageous to have a better CO.sub.2-balance as
compared to starting materials derived from oil.
[0006] J. Am. Chem. Soc. 2000, 122, 11553-11554 discloses that the
gold(III) salt AuCl.sub.3 catalysis an intramolecular ring closure
reaction of .omega.-alkynylfuran.
[0007] A. S. K. Hashmi et al., Adv. Synth. Catal. 2006, 348,
709-713 disclosed the first intermolecular reaction of a phenyl
alkyne with furan using binuclear gold(I) complexes. However, in
said reaction an almost equimolar amount of an alkenylfuran side
product is formed next to a substituted phenol.
[0008] A. Zeiler et al., Adv. Synth. Catal. 2015, 357, 1507-1514
disclosed an intermolecular furan-alkynye addition. Next to
phenylacetylene also different ethynyl aryl ethers are disclosed to
be reacted with dimethylfuran to yield alkenylfuran or the
respective phenol. In the document it is stressed that the oxygen
bound directly to the triple bond plays a crucial role in said
reaction.
[0009] N. Huguet et al. disclosed in Chem. Eur. J. 2013, 19,
6581-6585 an intermolecular gold(I) catalysed cyclization of furans
with alkynes. Next to aromatic substituted alkynes such as
phenylacetylene only unsubstituted short chain alkyl acetylenes
have been used.
[0010] WO 2015/110655 A1 discloses the reaction of ethyne with
2,5-dimethylfuran to yield 2,5-dimethylphenol. In this reaction,
however, also the corresponding 2,4-dimethylphenol is formed at
considerable amounts as side products leading to a mixture of
phenol isomers. WO 2015/110654 A1 discloses the reaction of
reaction of propyne with 2,5-dimethylfuran to yield
2,3,6-trimethylphenol. Propyne, however, is a starting product
which is difficult to handle and has a limited commercial
availability.
SUMMARY OF THE INVENTION
[0011] We have found that compounds of formula (I) can be easily
synthesized from 2,5-dimethylfuran in the presence of a gold(I)
complex.
[0012] The starting material, i.e. 2,5-dimethylfuran can be
obtained from biomass and therefore its use for the synthesis is
very advantageous in view of ecological aspects.
[0013] The process is also very advantageous in that the desired
product of formula (I) is formed at high selectivity and that side
products (of formula (IVa) and (IVb)) can be easily separated by a
further embodiment of the invention. Particularly surprising, it
has been found that no phenolic side products other than the
desired one are formed by said process.
[0014] The compounds of formula (I) can be used for the preparation
of 2,3,6-trimethylphenol, which is an important intermediate for
the synthesis of 2,3,5-trimethylbenzene-1,4-diol
(=2,3,5-trimethylhydroquinone) or of .alpha.-tocopherol,
respectively and, therefore, the invention is of technically and
economically high relevance.
[0015] Further aspects of the invention are subject of further
independent claims. Particularly preferred embodiments are subject
of dependent claims.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In a first aspect, the invention relates to a process of
preparing a compound of formula (I)
##STR00001## [0017] comprising the step of reacting compound of
formula (II) with compound of formula (III)
[0017] ##STR00002## [0018] wherein R.sup.1 represents a
C.sub.1-10-alkyl group or a C.sub.4-7-cycloalkyl group; in the
presence of a gold(I) complex.
[0019] 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.
[0020] A "C.sub.x-y-alkyl" group is an alkyl group comprising x to
y carbon atoms, i.e., for example, a C.sub.1-3-alkyl group is an
alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be
linear or branched. For example --CH(CH.sub.3)--CH.sub.2--CH.sub.3
is considered as a C.sub.4-alkyl group.
[0021] 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 said same label.
[0022] The expression "process of preparation" is a synonym for
"method of preparation" and can be used interchangeable to each
other.
[0023] The anion tetra(3,5-bis(trifluoromethyl)phenyl)borate is
abbreviated in the present document as "BAr.sub.F.sup.-" being
known to the person skilled in the art also by the abbreviation
"[BAr.sup.F.sub.4].sup.-".
[0024] Compound of formula (II) is 2,5-dimethylfuran which is
commercially available.
[0025] Compound of formula (II) can be obtained from biomass such
as cellulose. As biomass is a renewable raw material, the use of
2,5-dimethylfuran is very interesting from an ecological and
sustainability point of view. The process of obtaining
2,5-dimethylfuran from biomass, respectively from fructose, is
described in detail by Y. Roman-Leshkov et al., Nature 2007, 447,
982-985, the entire content of which is hereby incorporated by
reference. Fructose is obtainable from glucose, a building block in
cellulose.
[0026] The compounds of formula (III) are commercially available.
These ethers can be produced for example by the reaction of
propargylic alcohol with the respective dialkyl or dicycloalkyl
sulfide or sulphate, particularly dimethyl sulphate, or with the
respective alkyl or cycloalkyl iodide, particularly methyl iodide
such as disclosed in WO 2013/056073 A1.
[0027] Preferably R.sup.1 represents a C.sub.1-6-alkyl group,
particularly a C.sub.1-3-alkyl group, more preferably a methyl
group.
[0028] Said process of preparing a compound of formula (I)
comprises the step of reacting compound of formula (II) with
formula (III) in the presence of a gold(I) complex.
[0029] The gold(I) complex has preferably the formula [Au(I)OL]AN
wherein OL represents an organic ligand and AN represents a single
charged anion.
[0030] The gold(I) complex has preferably a single charged anion
(AN) which is selected from the group consisting of
[BX.sub.4].sup.-, [PX.sub.6].sup.-, [SbF.sub.6].sup.-,
[ClO.sub.4].sup.-, CF.sub.3COO.sup.-, sulfonates, particularly a
sulfonate of formula (AN-II),
tetra(3,5-bis(trifluoromethyl)-phenyl)borate (BAr.sub.F.sup.-),
tetraphenylborate, and anions of formula (AN-I)
##STR00003##
wherein X represents a halogen atom, particularly F or Cl; and
Y.sup.1 represents a phenyl or a C.sub.1-8-alkyl group which
preferably is substituted by at least one halogen atom.
[0031] Preferably Y.sup.1 represents a CF.sub.3 group. So,
preferably, the anions of formula (AN-I) is the anion of formula
(AN-Ia), i.e. the anion of bis(trifluoromethane)sulfonimide, which
is also known as triflimidic acid.
##STR00004##
[0032] Preferred sulfonates are halogenated anions of organic
sulfonic acids, particularly of trifluoromethanesulfonic acid,
which is also known as triflic acid. Therefore, the preferred
sulfonates are trifluoromethanesulfonates, which are also known as
triflates.
[0033] In a more preferred embodiment the anion (AN) in step b) is
an anion which is selected from the group consisting of
[SbF.sub.6].sup.-, [BX.sub.4].sup.-, triflate, and anions of
formula (AN-I).
[0034] A particularly preferred anion is [SbF.sub.6].sup.-.
[0035] It is preferred that the gold(I) complex has an organic
ligand (OL) which is either [0036] at least one phosphorous
containing ligand, particularly a phosphorous containing ligand
which is selected from the group consisting of formula (P1), (P2),
(P3), (P4), (P5), (P6), (P7) and (P8);
[0037] or [0038] at least an imidazole-2-ylidene ligand,
particularly
1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene
(=compound of formula (IM));
[0039] or [0040] at least an 1H-1,2,3-triazol ligand, particularly
of formula (TR-1) or (TR-2) or (TR-3), more particularly of formula
(TR-3);
[0040] ##STR00005## ##STR00006## [0041] wherein R.sup.10 and
R.sup.11 represent independently from each other either H or a
linear or branched C.sub.1-10-alkyl or C.sub.4-10-cycloalkyl group;
[0042] and [0043] wherein R.sup.12, R.sup.13, R.sup.14 and R.sup.15
represent independently from each other H or a linear or branched
C.sub.1-6-alkyl group; [0044] n stands for an integer of 1-6 and n'
stands for 0 or 1 or 2.
[0045] The organic ligand (OL) of formula (P4) is also known as
CyJohnPhos.
[0046] The synthesis of these organic ligands (OL) is known to the
person skilled in the art.
[0047] The Au(I) complex can be added to one or a mixture of the
starting material of compound of formula (II) and/or formula (III)
as such, i.e. particularly in the form of a gold(I) complex of
formula [Au(I)OL]AN, or the Au(I)-complex is formed in situ in one
of the starting material or the reaction mixture (before or after
the reaction has started).
[0048] The gold(I) complex is preferably formed in situ in the
reaction mixture.
[0049] Particularly, the gold(I) complex is prepared from a gold(I)
chloro complex and a silver(I) salt. The silver(I) salt is
preferably Ag(I)AN. The organic ligand is in this case either
present in the reaction of the gold(I) chloro complex with the
silver(I) salt or is part of the gold(I) complex. By this reaction
the desired gold(I) complex, i.e. preferably [Au(I)OL]AN, is
prepared. AgCl formed by this reaction as precipitate does not
interfere negatively with the reaction of preparing the compound of
formula (I).
[0050] Hence, the gold (I) complex is preferably of formula
[Au(I)OL]AN wherein OL represents an organic ligand and AN
represents a single charged anion and the gold (I) complex is
prepared by the reaction of Au(I)OLCl and AgAN.
[0051] Preferred Au(I) complexes of the formula [Au(I)OL]AN are
selected from the group consisting of
##STR00007##
and [Au(I)P6]AN-Ia, wherein P6 is the organic ligand of formula
(P6) and AN-Ia is the anion of formula (AN-Ia).
[0052] In another preferred embodiment, the gold (I) complex is of
formula [Au(I)OL]AN wherein OL represents an organic ligand and AN
represents a single charged anion and the gold (I) complex is
prepared by the reaction of Au(I)OLCl and NaAN. This reaction is
particularly preferred if AN is [BAr.sup.F.sub.4].sup.-.
[0053] The gold(I) complex is used typically in a molar ratio of
gold(I) complex to compound of formula (II) of 1:2 to 1:10'000,
particularly 1:10 to 1:3'000, preferably 1:25 to 1:3'000.
[0054] The molar ratio of compound of formula (II) to compound of
formula (III) is preferably between 0.05 and 10, more preferably
between 0.1 and 2, even more preferably between 0.2 and 1.5.
[0055] In another embodiment the molar ratio of compound of formula
(II) to compound of formula (III) is <1, preferably <0.8,
more preferably <0.5.
[0056] The most preferred compound of formula (I) is
2-(methoxymethyl)-3,6-dimethylphenol:
##STR00008##
[0057] The reaction is preferably carried out under normal pressure
(i.e. 1013 mbar). The reaction temperature is particularly between
0-50.degree. C., preferably between 15-30.degree. C.
[0058] The reaction is usually carried out in an inert solvent (or
mixture of inert solvents). Preferably the solvent (or the mixture
of solvents) has a pH of 7 or less than 7. Preferred solvents are
halogenated solvents, particularly dichloromethane,
1,2-dichloroethane, chloroform or 2,2,2-trifluoroethanol; or
toluene, ethyl acetate, cyclohexanone or acetone. More preferred,
the solvents are dichloromethane and 1,2-dichloroethane.
[0059] It has been observed that particularly mixtures of
dichloromethane and 2,2,2-trifluorethanol, preferably in an excess
of dichloromethane, more preferably a mixture of dichloromethane
with 5% by volume of 2,2,2-trifluoroethanol, are very suitable for
obtaining a high selectivity of compound of formula (I).
[0060] It has been observed that the reaction as described above
forms also compounds of formula (IVa) and/or formula (IVb) as
products of side reactions. However, it has been surprisingly found
that the formation of compound of formula (I) is much preferred
over the formation of these side products. Therefore, the compound
of formula (I) is formed at unexpected high selectivity and high
yield.
[0061] Said products can be identified/quantified by GC/MS and
NMR.
[0062] Compounds of formula (IVa) and/or formula (IVb) are,
therefore, formed only in minor amounts.
##STR00009##
[0063] Particular the total amount of compound of formula (IVa) and
(IVb) is at most 80% by weight, preferably at most 70% by weight,
more preferably at most 50% by weight, even more preferably at most
20% by weight, most preferably at most 10% by weight, relative to
the weight of compound of formula (I).
[0064] Particularly important is to note that no formation of
molecules of formula (I') have been observed in the above
reaction.
##STR00010##
[0065] This is very surprising as in case of the corresponding
reaction of ethyne with 2,5-dimethylfuran as disclosed in WO
2015/110655 A1 next to the desired 2,5-dimethylphenol considerable
amounts (I-a) also considerable amounts of 2,4-dimethylphenol (I-b)
are formed.
##STR00011##
[0066] These phenolic isomers (I-a)/(I-b) are very difficult to be
separated from each other due to their similar structures.
[0067] Therefore, in contrast to these reactions of the state of
the art, only one phenolic reaction product, i. e. compound of
formula (I), is formed in the process of the present invention.
[0068] It has been observed that the products of the side reaction,
i.e. compounds of formula (IVa) and/or formula (IVb), can be easily
separated from compound of formula (I) due to their strongly
different structure as compared to compound of formula (I).
[0069] In a preferred embodiment the process of preparing a
compound of formula (I) comprising the step of reacting compound of
formula (II) with compound of formula (III) as disclosed above
comprises a subsequent step a): [0070] a) separating the compound
of formula (I) from compound of formula (IVa) and/or formula
(IVb)
[0070] ##STR00012## [0071] wherein the wavy line represents a
carbon-carbon bond which is linked to the adjacent carbon-carbon
double bond so as to have said carbon-carbon double bond either in
the Z or in the E-configuration.
[0072] The separation can be achieved by different separation
methods such as distillation or chromatography.
[0073] Preferably compound of formula (I) is separated from
compound of formula (IVa) and/or (IVb) by chromatography,
particularly by using silica gel as stationary phase.
[0074] Chromatographic separation is known per se as standard
purification method. Particularly flash chromatography is suitable.
For industrial purposes particularly Simulated Moving Bed (SMB)
chromatography is very suitable for this separation.
[0075] By such an additional chromatographic separation, it can be
achieved to obtain the desired compound of formula (I) in pure
form, i.e. it is possible by optimizing said separation that the
compounds of formula (IVa) and/or formula (IVb) are reduced in
amount below the threshold of analytical detection.
[0076] Hence, in a further aspect the invention relates to compound
of formula (I).
[0077] In an even further aspect the invention relates to a
composition comprising the compound of formula (I) and at least the
compound of formula (IVa) or (IVb)
##STR00013## [0078] wherein R.sup.1 represents a C.sub.1-10-alkyl
group or a C.sub.4-7-cycloalkyl group and the wavy line represents
a carbon-carbon bond which is linked to the adjacent carbon-carbon
double bond so as to have said carbon-carbon double bond either in
the Z or in the E-configuration.
[0079] As mentioned above already for compound of formula (I), it
is preferred that that R.sup.1 represents a C.sub.1-6-alkyl group,
preferably a C.sub.1-3-alkyl group, more preferably a methyl
group.
[0080] It is further preferred that in said composition the total
amount of compound of formula (IVa) and (IVb) is at most 80% by
weight, preferably at most 70% by weight, more preferably at most
50% by weight, even more preferably at most 20% by weight, most
preferably at most 10% by weight, relative to the weight of
compound of formula (I).
[0081] By using separation method as mentioned above the total
amount of compound of formula (IVa) and (IVb) can be easily further
reduced. Therefore, it is easily achievable that the total amount
of compound of formula (IVa) and (IVb) after additional separation
step, such as chromatography, is at most 1% by weight, preferably
at most 0.5% by weight, more preferably at most 0.1% by weight,
relative to the weight of compound of formula (I). In a preferred
embodiment pure compound of formula (I) is obtained after the
separation step.
[0082] Compounds of formula (I), particularly been prepared
according to the process as disclosed above in great detail, are
particularly useful as intermediate for the synthesis of
2,3,6-trimethylphenol, which is an important intermediate for the
synthesis of 2,3,5-trimethylbenzene-1,4-diol
(=2,3,5-trimethylhydroquinone) or of .alpha.-tocopherol,
respectively. Therefore, another aspect of the present invention
relates to a process of reducing a compound of formula (I)
##STR00014## [0083] by a reducing agent in the presence of a
heterogeneous metal catalyst to yield a compound of formula (A)
[0083] ##STR00015## [0084] wherein the metal is selected from the
group consisting of Ni, Fe, Ir, Pd, Pt, Rh and Ru; [0085] wherein
R.sup.1 represents a C.sub.1-10-alkyl group or a
C.sub.4-7-cycloalkyl group.
[0086] Compound of formula (I) is reduced in the above process by a
reducing agent.
[0087] In one preferred embodiment the reducing agent is molecular
hydrogen. In other words, in one embodiment the compound of formula
(I) is hydrogenated by molecular hydrogen in the presence of a
heterogeneous metal catalyst.
[0088] In another preferred embodiment the reducing agent is a
transfer hydrogenation agent. In other words, in another embodiment
the compound of formula (I), is transfer hydrogenated by a transfer
hydrogenation agent. Said transfer hydrogenation agent is
preferably formic acid and/or a formic acid salt.
[0089] The compound of formula (I) is reduced by a reducing agent
in the presence of a heterogeneous metal catalyst wherein the metal
is selected from the group consisting of Ni, Fe, Ir, Pd, Pt, Rh and
Ru.
[0090] It is preferred that the metal of the heterogeneous metal
catalyst comprises at least one of the metals selected from the
group consisting of Ni, Fe, Ir, Pd, Pt and Rh. The heterogeneous
metal catalyst can be a catalyst comprising more than one of the
mentioned metals.
[0091] Particularly, the heterogeneous metal catalyst comprises Pd
and Pt as metal.
[0092] It is preferred that the metal of the heterogeneous metal
catalyst is palladium.
[0093] A wide variety of heterogeneous metal catalysts are known.
Particularly useful are heterogeneous metal catalyst which are on a
carrier or 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, alumina, and silica. The preferred support/carrier
material is carbon.
[0094] 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. 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 BI or Sulzer Mellapak. The
structured packings made of expanded metal are also advantageous,
for example structured packings of the type Montz BSH.
[0095] It is preferred that the heterogeneous metal catalyst is a
palladium catalyst, particularly a palladium on carbon catalyst
(Pd/C).
[0096] The catalytic metal loading (i.e. 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 heterogeneous metal catalyst is palladium on carbon
catalyst (Pd/C) of which 5% by weight is palladium (i.e.
loading=5%).
[0097] The reduction can be carried out in the presence or absence
of solvents. Suitable solvents are particularly those in which the
compound of formula (I) is soluble. Particularly, the solvent is an
organic solvent, preferably a solvent selected from the group
consisting of alcohols, preferably the alcohol of formula
R.sup.1OH, or ethers, preferably dialkyl ether or cyclic ethers,
preferably tetrahydro-furan. R.sup.1OH is the alcohol which is
formed in the reduction reaction as mentioned above.
[0098] Furthermore, suitable additives may be added to the reaction
mixture of the compound of formula (I), the heterogeneous metal
catalyst and the reducing agent. Particularly, organic acids,
preferably acetic acid, can be added to the mixture before or
during the reduction.
[0099] The reduction is performed typically at temperatures of
between 20 and 80.degree., particularly between 30 and 50.degree.
C., and preferably under a pressure. In case of use of molecular
hydrogen, it is preferred that the reduction is carried out under a
pressure of hydrogen of between 2 and 20 bar, preferably of between
3 and 7 bar.
[0100] The reduction is performed in a suitable vessel. The
reduction can be made batchwise or continuously. Suitable reactors
for industrial scale are known.
[0101] It is preferred that the weight ratio of the heterogeneous
metal catalyst to the compound of formula (I) is 0.01% to 20%,
particularly 1% to 10%.
[0102] It has been observed that the process as described above
yields efficiently a compound of formula (A)
##STR00016##
[0103] It has been also observed that the above process is
surprisingly suited for the reduction of compound (I) as it has
been observed that reduction of molecules having a very similar
chemical structure as compared with compound of formula (I) could
not be reduced to the corresponding (poly)alkylphenols.
[0104] As mentioned above, 2,3,6-trimethylphenol, i.e. compound of
formula (A), is an important intermediate for the synthesis of
2,3,5-trimethylbenzene-1,4-diol (=2,3,5-trimethylhydroquinone) or
of .alpha.-tocopherol, respectively.
[0105] Hence, a further aspect of the present invention is a
process for the manufacture of the compound of formula (C) from
compound of formula (I) comprising the following steps [0106] a')
reducing the compound of formula (I) by the process as disclosed
above in great detail to yield a compound of formula (A);
[0106] ##STR00017## [0107] b') oxidizing the compound of formula
(A) to yield a compound of formula (B) by an oxidizing agent
[0107] ##STR00018## [0108] c') reducing the compound of formula (B)
to yield a compound of formula (C) by a reducing agent
##STR00019##
[0109] In step b') the compound of formula (A) is oxidized to the
compound of formula (B). The oxidation is preferably carried out by
any suitable method known in the art, for example: with air using
salcomine as catalyst in ethanol according to the procedure
published by A. Stocker, W.-D. Woggon, A. Ruttimann, Helv. Chim.
Acta 1993, 76, 1729-1738, or by copper and molecular oxygen as
described in EP 0127888 A1 or by the use of a heteropoly acid and
oxygen as described by Kholdeeva et al in Journal of Molecular
Catalysis, 75 (1992) 235-244, the entire content of which is hereby
incorporated by reference.
[0110] In step c') the compound of formula (B) is reduced to
compound of formula (C). The reduction can be performed by
hydrogenation or 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.
[0111] Compounds of formula (C) can be used directly in various
fields or can be used as important starting materials for the
synthesis of compounds suitable for the synthesis of compounds
useful in pharmaceuticals, food or feed supplements, cosmetics, or
flavors and flagrances.
[0112] Particularly important is the use of compound of formula (C)
as antioxidant, in plastics, adhesives, inks, composites, or in
organisms.
[0113] The compound of formula (A) is particularly important as it
can be used as a starting material for the synthesis of
.alpha.-tocopherol.
[0114] Therefore, in a further aspect, the invention relates to a
process for the manufacture of compound of formula (D) from
compound of formula (I) comprising the steps [0115] a') hydrogenate
compound of formula (I) by the process as disclosed above in great
detail to yield a compound of formula (A);
[0115] ##STR00020## [0116] b') oxidizing the compound of formula
(A) to yield a compound of formula (B) by an oxidizing agent
[0116] ##STR00021## [0117] c') reducing the compound of formula (B)
to yield a compound of formula (C) by a reducing agent
[0117] ##STR00022## [0118] d') condensing isophytol with the
compound of formula (C) to yield a compound of formula (D);
##STR00023##
[0119] In step d') isophytol
(=3,7,11,15-tetramethylhexadec-1-en-3-ol) is condensed with a
compound of formula (C) to yield a compound of formula (D).
Isophytol and a compound of formula (C), described as step d), is
known by the person skilled in the art. For this condensation a
series of catalysts may be used such as ZnCl.sub.2/mineral acid,
BF.sub.3/AlCl.sub.3, Fe/HCl, trifluoroacetic acid or boric
acid/carboxylic acid as well as indium(III) or scandium(III) salts
as disclosed in WO 2005/121115 A1. Furthermore, suitable catalysts
are heteropoly acids, particularly 12-tungstophosphoric acid or
12-tungstosilicic acid such as disclosed in EP 0 970 953 A1, the
entire content of which is hereby incorporated by reference.
EXAMPLES
[0120] The present invention is further illustrated by the
following experiments.
Formation of Gold (I) Complex
[0121] In a glovebox 380.2 mg
chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I)
(=0.61 mmol) and 210.4 mg silverhexafluoroantimonate (=0.61 mmol)
or 543 mg sodium tetra(3,5-bis(trifluoromethyl)phenyl)borate (=0.61
mmol) and 61.3 .mu.l benzonitrile are weighed in a 25 ml round
bottom flask which is equipped with a magnetic stirring bar and
argon supply. During this procedure the gold (I) complex
[Au(I)IM]SbF.sub.6 respectively [Au(I)IM]BAr.sub.F, IM being the
organic ligand of formula (IM) has been formed.
Formation of 2-(methoxymethyl)-3,6-dimethylphenol
[0122] To the above mentioned mixture 10 ml of dichloromethane or a
mixture of dichloromethane/2,2,2-trifluorethanol (95/5 vol %) are
admixed outside the glovebox and 5.364 ml 2,5-dimethylfuran (=50
mmol), respectively 1.072 ml (=10 mmol) (="DMF") are added and
cooled to 0.degree. C., followed by addition of 0.87 ml
methylpropargylether (=10 mmol) (="MPE") The reaction mixture has
turned blue and darkens on further agitation. The reaction mixture
is agitated at 23.degree. C. under argon for a further 120
hours.
[0123] After concentrating under reduced pressure at 40.degree. C.
and 20 mbar the residue formed has been taken up in 60 ml of
dichloromethane.
[0124] The dried residue has been analyzed by gas chromatography.
The amounts of 2-(methoxymethyl)-3,6-dimethylphenol (="(I)") and
the total amounts of the respective alkenylfuran compounds of
formula (IVa) or (IVb) (R.sup.1.dbd.CH.sub.3) ("(IVa)/(IVb)") have
been indicated in table 1 in GC-area-%.
TABLE-US-00001 TABLE 1 DMF/MPE [(I)] [(IVa)/(IVb)] [ ( IVa ) / (
IVb ) ] [ [ ( I ) ] ] ##EQU00001## Ex. Catalyst [w/w] Solvent [%]
[%] [%] 1 [Au(I)IM]SbF.sub.6 5:1 DCM/TFE.sup.1 42 1 2.4 2
[Au(I)IM]BAr.sub.F 5:1 DCM/TFE.sup.1 42 30 71 3 [Au(I)IM]SbF.sub.6
5:1 DCM.sup.2 48 31 65 4 [Au(I)IM]SbF.sub.6 5:1 TFE.sup.3 33 15 45
5 [Au(I)IM]SbF.sub.6 5:1 DCM.sup.2 32 24 75 6 [Au(I)IM]BAr.sub.F
0.8:1 DCM.sup.2 51 8 16 Formation of
2-(methoxymethyl)-3,6-dimethylphenol .sup.1DCM/TFE =
dichloromethane/2,2,2-trifluorethanol (95/5 w/w) .sup.2DCM =
dichloromethane .sup.3TFE = 2,2,2-trifluorethanol (95/5 w/w)
[0125] The residue has been in a further step purified by
chromatography over 40 g silica gel column (particle size: 40-63
.mu.m) with cyclohexane/ethylacetate (95:5 vol/vol) as eluent to
yield pure 2-(methoxymethyl)-3,6-dimethylphenol.
2-(methoxymethyl)-3,6-dimethylphenol has been identified by
.sup.1H-NMR, .sup.13C NMR and GC/MS.
[0126] For GC/MS analysis, the sample was treated with
N,O-bis(trimethyl-silyl)trifluoroacetamide (BSTFA) and pyridine.
When in the GC/MS analysis a Si(CH.sub.3).sub.3 fragment of a
particular species was observed, this was an indication for the
presence of a free hydroxylgroup, such as in phenol. In the
hydroarylated products (formula (IVa) or (IVb)), the presence of
trimethylsilyl fragments was not observed.
2-(methoxymethyl)-3,6-dimethylphenol
[0127] GC/MS (M.sup.+=166 g/mol). Silylation observed
[0128] .sup.1H NMR (300 MHz, CDCl.sub.3, .delta. in ppm): 6=2.20
(s, 3H); 2.21 (s, 3H); 3.45 (s, 3H); 4.71 (s, 2H); 6.59 (d, J=7.56
Hz, 1H); 6.94 (d, J=7.56 Hz, 2H); 8.01 (s, 1H).
[0129] .sup.13C-NMR (75 MHz, CDCl.sub.3, 5 in ppm): 6=15.6; 19.1;
58.3; 70.8; 119.4; 121.3; 123.2; 129.9; 133.4; 154.8.
Hydroarylated Compound of Formula (IVa) or (IVb):
[0130] GC-MS: M.sup.+=166.1 g/mol. No silylation observed.
[0131] .sup.1H NMR (300 MHz, CDCl.sub.3, .delta. in ppm): 6=2.20
(s, 3H); 2.33 (s, 3H); 3.35 (s, 3H); 4.09 (d, J=0.75 Hz, 2H); 5.14
(d, J=1.59; 1H); 5.5.22 (d, J=1.59 Hz, 1H); 6.00 (s, 1H).
[0132] .sup.13C-NMR (75 MHz, CDCl.sub.3, .delta. in ppm): 56=13.2;
13.3; 57.8; 75.3; 105.9; 113.2; 119.3; 137.9; 146.8; 149.4.
Formation of 2,3,6-trimethylphenol (Example 7)
##STR00024##
[0134] 2-(methoxymethyl)-3,6-dimethylphenol (32 mg) (as prepared
above) was dissolved in methanol (1.0 g) and 5% palladium on carbon
(Evonik E 101 N/D, 3 mg) was added. The reactor was sealed and
purged three times with nitrogen and three times with hydrogen. The
mixture was stirred at 40.degree. C. under 5 bar hydrogen pressure
for 22 hours. An additional 3 mg of 5% palladium on carbon was
added and the mixture was stirred at 40.degree. C. under 5 bar
hydrogen pressure for a further 22 hours. The pressure was
released, the catalyst was removed by filtration and the mixture
evaporated under reduced pressure to give a crude product. GC-MS
analysis showed full conversion and 98.5% purity product (yield
98%).
Comparative Examples
[0135] 5-methyl-1,3-dihydroisobenzofuran-4-ol or
3-(methoxymethyl)phenol, respectively, have been submitted to the
same reduction conditions as for example 7 with the object to yield
2,3,6-trimethylphenol, or m-cresol, respectively. However, in both
cases, the desired product has not been detected.
##STR00025##
* * * * *